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Papers by David Nichols
Neuroscience Letters, Nov 1, 2011
This study was designed to determine whether a 5-HT 2C receptor antagonist could induce a conditi... more This study was designed to determine whether a 5-HT 2C receptor antagonist could induce a conditioned place preference indicative of reward and/or abuse potential. Here, we present the first evidence that a selective 5-HT 2C receptor antagonist, 6-chloro-5-ethoxy-N-(pyridin-2yl)indoline-1-carboxamide hydrochloride (CEPC), can potentiate a low dose (0.5 mg/kg) amphetamine-induced positive conditioned place preference (CPP). CEPC did not produce any CPP given alone at doses of either 2.0 or 4.0 mg/kg, whereas low dose amphetamine alone produced only a slight, but statistically nonsignificant, place preference. These studies suggest that 5-HT 2C receptor antagonists can indirectly potentiate the rewarding effects of amphetamine, and perhaps other psychostimulants. If the results can be translated to man, putative 5-HT 2C receptor antagonist treatments for anxiety or depression may enhance or potentiate the rewarding effects of drugs of abuse such as amphetamine, which release dopamine.
Journal of Medicinal Chemistry, 1984
of 1 pL/min) were made into the left ascending median forebrain bundle (MFB) in the lateral hypot... more of 1 pL/min) were made into the left ascending median forebrain bundle (MFB) in the lateral hypothalamus using the stereotaxic coordinates of the DeGroot% brain atlas (A, +4.6; L, 1.9; V,-2.7). 6-OHDA was made up in distilled water containing 0.2 pg/pL of ascorbic acid and kept in ice throughout the injection procedure. Three to four weeks after lesioning, the rats were tested for rotational behavior in response to apomorphine, 0.25 mg/kg SC. Rats that turned 8-10 times per minute during peak activity were selected for further drug trials. Rotational behavior was determined in automatically recording rotometers, details of which were recently described.30 Groups of four to eight rats were injected sc with the test compounds and then placed immediately into the rotometer. Rotational behavior was continuously recorded until its cessation. The results are expressed as total number of t,urns. Acknowledgment. The authors express their appreciation to Dr. G. Shilling and his associates for microanalytical and spectral data. The skillful assistance of M. Asselin and J. Csakvary in the chemical synthesis and N. Lapeyre and Ida Vozzella in the pharmacological studies is gratefully acknowledged.
Drug Testing and Analysis, Jun 6, 2016
Lysergic N,N-diethylamide (LSD) is perhaps one of the most intriguing psychoactive substances kno... more Lysergic N,N-diethylamide (LSD) is perhaps one of the most intriguing psychoactive substances known and numerous analogs have been explored to a varying extent in previous decades. In 2013, N 6-allyl-6-norlysergic acid diethylamide (AL-LAD) and (2'S,4'S)-lysergic acid 2,4dimethylazetidide (LSZ) have appeared on the 'research chemicals' / new psychoactive substances (NPS) market in both powdered and blotter form. This study reports the analytical characterization of powdered AL-LAD and LSZ tartrate samples and their semi-quantitative determination on blotter paper. Included in this study was the use of nuclear magnetic resonance spectroscopy, gas chromatography mass spectrometry (MS), low and high-resolution electrospray MS(/MS), high performance liquid chromatography diode array detection and GC solid-state infrared analysis. One feature shared by serotonergic psychedelics, such as LSD, is the ability to mediate behavioral responses via activation of 5-HT 2A receptors. Both AL-LAD and LSZ displayed LSD-like responses in male C57BL/6J mice when employing the head-twitch response (HTR) assay. AL-LAD and LSZ produced nearly identical inverted-U-shaped dose-dependent effects, with the
Journal of Psychopharmacology, 2019
Background: In the past few years, the issue of ‘microdosing’ psychedelics has been openly discus... more Background: In the past few years, the issue of ‘microdosing’ psychedelics has been openly discussed in the public arena where claims have been made about their positive effect on mood state and cognitive processes such as concentration. However, there are very few scientific studies that have specifically addressed this issue, and there is no agreed scientific consensus on what microdosing is. Aim: This critique paper is designed to address questions that need to be answered by future scientific studies and to offer guidelines for these studies. Approach: Owing to its proximity for a possible approval in clinical use and short-lasting pharmacokinetics, our focus is predominantly on psilocybin. Psilocybin is allegedly, next to lysergic acid diethylamide (LSD), one of the two most frequently used psychedelics to microdose. Where relevant and available, data for other psychedelic drugs are also mentioned. Conclusion: It is concluded that while most anecdotal reports focus on the posit...
Proceedings of the National Academy of Sciences of the United States of America, Jan 11, 2016
Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the hum... more Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD's marked effects on the visual cortex did not significantly correlate with the drug's other characteristic e...
Arkivoc, 2011
To assess the importance of conformation and placement of the β-substituent of agonist ligands ta... more To assess the importance of conformation and placement of the β-substituent of agonist ligands targeted to the D 1 dopamine receptor, (±)-trans-6,6a,7,8,13,13a-hexahydrobenzo[e]chromeno [3,4-b]azepine-2,3-diol 5 and (±)-trans-6,6a,7,8,9,13b-hexahydrobenzo[d]chromeno[3,4b]azepine-2,3-diol 6 were synthesized as ring-expanded analogues of the high affinity D 1 dopamine receptor selective agonist doxanthrine, using a novel tetrahydrobenzazepine ringforming strategy. Compounds 5 and 6 had only micromolar affinity at the D 1 receptor. Molecular modeling show deviations in the orientation of the accessory phenyl ring between 4 and its ring expanded analogs 5 and 6. Furthermore, the additional methylene group in the azepine ring may cause an unfavorable steric intrusion into the receptor binding process. These conformational differences suggest that the placement of the accessory phenyl ring must be well defined.
Beilstein Journal of Organic Chemistry, 2012
A strategy to replace the ethylamine side chain of 2,5-dimethoxy-4-iodoamphetamine (DOI, 1a), and... more A strategy to replace the ethylamine side chain of 2,5-dimethoxy-4-iodoamphetamine (DOI, 1a), and 2,5-dimethoxy-4-bromoamphetamine (DOB, 1b) with a cyclopropylamine moiety was successful in leading to compounds with high affinity at the 5-HT2 family of receptors; and the more potent stereoisomer of the cyclopropane analogues had the expected (−)-(1R,2S)-configuration. Screening for affinity at various serotonin receptor subtypes, however, revealed that the cyclopropane congeners also had increased affinity at several sites in addition to the 5-HT2A and 5-HT2B receptors. Therefore, at appropriate doses – although (−)-4 and (−)-5 may be useful as tools to probe 5-HT2 receptor function – one would need to be mindful that their selectivity for 5-HT2A receptors is somewhat less than for DOI itself.
Journal of Pharmaceutical Sciences, 1971
IJ Various ring-methoxylated 1-phenyl-2-propanols and 1-phenyl-2-propanones were synthesized and ... more IJ Various ring-methoxylated 1-phenyl-2-propanols and 1-phenyl-2-propanones were synthesized and pharmacologically evaluated. Most compounds had depressantlike activity. The ketones were readily reduced by rabbit liver microsomes. No reductase activity was found in rat and mouse liver preparations. Partition coefficients were determined, and a linear correlation between LRA6,'s (loss of righting ability in 50% of the mice) and partition coefficients was observed for six of the compounds investigated. Keyphrases 0 1-Phenyl-2-propanols, 1-phenyl-2-propanones,
![Research paper thumbnail of trans-2,3-Dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline: Synthesis, Resolution, and Preliminary Pharmacological Characterization of a New Dopamine D1 Receptor Full Agonist](https://attachments.academia-assets.com/105274747/thumbnails/1.jpg)
](Journal of Medicinal Chemistry, 2006
Synthesis, 2009
An efficient synthesis of the dopamine D 1 selective full agonist dihydrexidine has been achieved... more An efficient synthesis of the dopamine D 1 selective full agonist dihydrexidine has been achieved in high yields and requiring no chromatographic separations via a facilitated intramolecular Henry cyclization of a (nitropropyl)benzophenone and subsequent diastereomerically selective reduction of the resulting tricyclic nitroalkene.
Molecular pharmacology, 2012
To refine further the structure-activity relationships of D(1) dopamine receptor agonists, we inv... more To refine further the structure-activity relationships of D(1) dopamine receptor agonists, we investigated the roles of three conserved serine residues [Ser198(5.42), Ser199(5.43), and Ser202(5.46)] in agonist binding and receptor activation. These transmembrane domain 5 (TM5) residues are believed to engage catechol ligands through polar interactions. We stably expressed wild-type or mutant (S198A, S199A, and S202A) D(1) receptors in human embryonic kidney cells. These receptors were expressed at similar levels (approximately 2000 fmol/mg) and bound the radioligand [(3)H]R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390), although S198A and S199A displayed significant losses of affinity compared with that for wild-type receptors. The endogenous agonist, dopamine, had losses of potency at each of the mutant receptors. We tested cyclohexyl-substituted isochroman, carbocyclic, and chroman bicyclic dopamine analogs and found that the mutations aff...
ChemInform, 2010
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
NIDA research monograph, 1978
Psychopharmacology, 1993
Fenfluramine, a phenalkylamine with serotonin (5-HT) releasing properties, decreases motor activi... more Fenfluramine, a phenalkylamine with serotonin (5-HT) releasing properties, decreases motor activity in rats. The following studies assessed the contribution of 5-HT release to the behavioral effects of fenfluramine and norfenfluramine using a behavioral pattern monitor that simultaneously assesses locomotor and investigatory behavior. First, both fenfluramine and its active metabolite d-norfenfluramine dose-dependently reduced locomotor and investigatory activity. The norfenfluramine-induced reduction in activity was not antagonized by pretreatment with the 5-HT uptake inhibitor fluoxetine or the 5-HT synthesis inhibitor p-chlorophenylalanine, drugs that reduce drug-induced 5-HT release. Second, the d-and/-enantiomers of norfenfluramine were nearly equipotent at reducing behavioral activity, although d-norfenfluramine is more potent as a 5-HT releasing agent. Third, p-chloroamphetamine, a drug that shares the 5-HT releasing properties of fenfluramine produced locomotor hyperactivity in the same paradigm. Previous studies indicate that other 5-HT releasing phenalkylamines have behavioral effects resembling those of p-chloroamphetamine rather than those of fenfluramine. Finally, a structurally related drug, 4-methoxy-5-methyl-aminoindan (MMAI), produced dose-dependent reductions in behavioral activity that are similar to the effects of fenfluramine. The behavioral effects of MMAI were not antagonized by fluoxetine or by the 5-HT receptor antagonist methiothepin. These data suggest that the decrease in activity induced by fenfluramine, norfenfluramine and the related drug MMAI is not related to 5-HT release.
Psychopharmacology, 2012
RATIONALE-Ayahuasca is a psychoactive tea prepared from a combination of plants that contain a ha... more RATIONALE-Ayahuasca is a psychoactive tea prepared from a combination of plants that contain a hallucinogenic tryptamine and monoamine oxidase inhibitors (MAOIs). Behavioral Pattern Monitor (BPM) experiments demonstrated that the combination of 5-methoxy-N,Ndimethyltryptamine (5-MeO-DMT) and a behaviorally inactive dose of an MAO A inhibitor such as harmaline or clorgyline induces biphasic effects on locomotor activity in rats, initially reducing locomotion and then increasing activity as time progresses. OBJECTIVES-The present study investigated whether the biphasic locomotor profile induced by the combination of 5-MeO-DMT and an MAOI is a consequence of a reduction in the rate of 5-MeO-DMT metabolism. This hypothesis was tested using a deuterated derivative of 5-MeO-DMT (, , ,-tetradeutero-5-MeO-DMT) that is resistant to metabolism by MAO. RESULTS-Confirming our previous findings, 1.0 mg/kg 5-MeO-DMT (s.c.) had biphasic effects on locomotor activity in rats pretreated with a behaviorally inactive dose of the nonselective MAOI pargyline (10 mg/kg). Administration of 5-MeO-DMT alone, even at doses greater than 1.0 mg/kg, produced only reductions in locomotor activity. Although low doses of , , ,-tetradeutero-5-MeO-DMT (0.3 and 1.0 mg/kg, s.c.) produced only hypoactivity in the BPM, a dose of 3.0 mg/kg induced a biphasic locomotor profile similar to that produced by the combination of 5-MeO-DMT and an MAOI. Receptor binding studies demonstrated that deuterium substitution had little effect on the affinity of 5-MeO-DMT for a wide variety of neurotransmitter binding sites. CONCLUSIONS-The finding with , , ,-tetradeutero-5-MeO-DMT indicates that the hyperactivity induced by 5-MeO-DMT after MAO inhibition is a consequence of reduced metabolism of 5-MeO-DMT, leading to prolonged occupation of central serotonin receptors. These results demonstrate that deuterated tryptamines may be useful in behavioral and pharmacological studies to mimic the effects of tryptamine/MAOI combinations.
Psychopharmacology, 2012
Rationale Preclinical evidence indicates that D 1 dopamine receptor full agonists have potential ... more Rationale Preclinical evidence indicates that D 1 dopamine receptor full agonists have potential as therapeutic agents for a variety of neurological conditions. Dihydrexidine (DHX) was the first high potency selective D 1 dopamine receptor full agonist and has been studied as a possible treatment for Parkinson's disease (PD). Recently, we discovered doxanthrine (DOX), an oxygen bioisostere of DHX that has even greater selectivity for the D 1 dopamine receptor. Objectives Using the unilateral 6-hydroxydopamine-lesioned rat model of PD, DOX and DHX were compared at several doses (0.625, 1.25, 2.5, or 5.0 mg/kg) for their ability to elicit contralateral rotation by either intraperitoneal injection or oral gavage. Results After intraperitoneal administration, both DOX and DHX showed robust contralateral rotation at doses of 2.5 and 5.0 mg/kg compared to vehicle. In addition, after intraperitoneal administration at doses of 2.5 and 5.0 mg/kg, DHX had a significantly longer duration of action than DOX (p<0.05). Areas under the curves (AUC) for DOX and DHX were not significantly different, however, indicating that DOX and DHX have similar potency after intraperitoneal administration. By contrast, after oral administration, 2.5 and 5.0 mg/kg of DOX produced significant contralateral rotations (p<0.05), whereas DHX showed no significant activity after oral administration of any dose. Conclusion These results demonstrate that although DHX and DOX have similar activity after intraperitoneal administration, DOX demonstrated greater activity after oral administration compared to DHX. Despite its catechol functionality, DOX may possess sufficient oral availability for development as a human therapeutic agent.
Pharmacology Biochemistry and Behavior, 1989
transiently alters biogenic amines and metabolites in mouse brain and heart. PHARMACOL BIOCHEM BE... more transiently alters biogenic amines and metabolites in mouse brain and heart. PHARMACOL BIOCHEM BEHAV 34(2) 223-227, 1989.-(-'-)-3,4-Methylenedioxymethamphetamine (MDMA) (10, 20, and 40 mg/kg) was administered to male CF-1 mice which were sacrificed 3, 6, or 24 hours posttreatment for analysis of brain and cardiac biogenic amines and metabolites. In contrast to reported effects of MDMA in the rat, the highest dose of MDMA transiently elevated mouse brain 5-hydroxytryptamine (5-HT) 3 hours following drug treatment. Levels of dopamine were not significantly affected. 5-Hydroxyindoleacetic acid and dihydroxyphenylacetic acid were significantly lowered by MDMA at the two early time points. The highest dose of MDMA produced a transient depletion of norepinephrine in mouse brain and heart tissue. Only the effects of MDMA on cardiac norepinephrine were prevented by pretreatment of animals with desipramine. A regimen consisting of four daily doses of 40 mg/kg MDMA only produced significant declines in 5-HIAA, dopamine and homovanillic acid levels one week following the last dose. These data confirm previous reports that mice are resistant to the neurotoxic effects of MDMA suggesting that a species variation in response to MDMA exists. MDMA Biogenic amines Neurotoxicity
Neuropsychopharmacology, 1994
Robust individual differences in social behavior have been ob tained by selectively breeding Inst... more Robust individual differences in social behavior have been ob tained by selectively breeding Institute for Cancer Research mice for high and low levels of aggression. As previously shown, when paired with a non-selected, group-housed partner mouse, NC900 mice exhibit isolation-induced aggression. Conversely, NClDO mice fail to attack, freezing upon social contact. Previous studies have established that NClDO mice have lower dopamine concentrations in nucleus accumbens and caudate nucleus, with increased dopamine receptor densities in these same regions. Thus, we wished to determine the effect of administration of a dopamine receptor agonist on social behavior. Mice of both lines were administered 0, 1, 3, or lD mglkg (SC) of the full efficacy Dl receptor agonist dihydrexidine, and their behavior was assessed in a social interaction test.
Nature Reviews Neuroscience, 2013
Life Sciences, 1978
The hallucinogen analog tram-2-(2,5-dimethoxy-4-methylphenyl)-cyclopropylamiae (DMCPA) was resolv... more The hallucinogen analog tram-2-(2,5-dimethoxy-4-methylphenyl)-cyclopropylamiae (DMCPA) was resolved into its two optical isomers. Eaaminatioa of selected behavioral, profiles in mice and cats clearly showed that the levorotatory isomer of DMCPA possesses atereoaelective activity when compared with the dextro isomer. The results parallel those obtained using the isomers of the known hallucinogen, DOM (STP) in the same animal models. Comparison of the optical rotatory dispersion (ORD) curves for the N-(5-bromosalicylidene) derivatives of DMCPA and traps-2pheaylcyclopropylamine (tranylcypromlne) of known absolute configuration established the configuration of DMCPA to be (-)-1R,2S. This stereoselective activity and proof of absolute configuration lend strong support to a new model of the hallucinogen receptor. The proposed model suggests possible structural similarities between LSD and phenethylamine hallucinogens. Recently we proposed a new way to view the possible structural relationship between LSD and hallucinogens of the phenethylamine class such as mescaline or DOM (STP) (1). We used our hypothesis to predict that the active enantiomer of rigid tram-2-phenylcyclopropylamine hallucinogens would possess the 1R,2S absolute configuration (e .g. figure 2c). We now report data which confirm this prediction and lend support to our view of the hallucinogen receptor. Materials and Methode Drugs. The (+) and (-) isomers of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane hydrochloride (DOM) were obtained through the cooperation of the Research Technology Branch, National Institute on Drug Abuse, and had [a]D~-I-17 .1°and-17.7°, respectively. The (+) and (-) isomers of tram-2-(2,5-dimethoxy-4methylphenyl)-cyclopropylamine hydrochloride (DMCPA) were prepared in our laboratories by synthesis and chemical resolution and had [a]Da+55 .2°and-55.6°, respectively. The (+) and (-) isomers of traaylcypromine were donated by Smith, Rline and French Laboratories. Animals. Adult male Swiss-Webeter mice (30-40 g) were obtained from Laboratory Supply Co ., Inc. (Indianapolis, In .) and were housed in groups of ten and
Neuroscience Letters, Nov 1, 2011
This study was designed to determine whether a 5-HT 2C receptor antagonist could induce a conditi... more This study was designed to determine whether a 5-HT 2C receptor antagonist could induce a conditioned place preference indicative of reward and/or abuse potential. Here, we present the first evidence that a selective 5-HT 2C receptor antagonist, 6-chloro-5-ethoxy-N-(pyridin-2yl)indoline-1-carboxamide hydrochloride (CEPC), can potentiate a low dose (0.5 mg/kg) amphetamine-induced positive conditioned place preference (CPP). CEPC did not produce any CPP given alone at doses of either 2.0 or 4.0 mg/kg, whereas low dose amphetamine alone produced only a slight, but statistically nonsignificant, place preference. These studies suggest that 5-HT 2C receptor antagonists can indirectly potentiate the rewarding effects of amphetamine, and perhaps other psychostimulants. If the results can be translated to man, putative 5-HT 2C receptor antagonist treatments for anxiety or depression may enhance or potentiate the rewarding effects of drugs of abuse such as amphetamine, which release dopamine.
Journal of Medicinal Chemistry, 1984
of 1 pL/min) were made into the left ascending median forebrain bundle (MFB) in the lateral hypot... more of 1 pL/min) were made into the left ascending median forebrain bundle (MFB) in the lateral hypothalamus using the stereotaxic coordinates of the DeGroot% brain atlas (A, +4.6; L, 1.9; V,-2.7). 6-OHDA was made up in distilled water containing 0.2 pg/pL of ascorbic acid and kept in ice throughout the injection procedure. Three to four weeks after lesioning, the rats were tested for rotational behavior in response to apomorphine, 0.25 mg/kg SC. Rats that turned 8-10 times per minute during peak activity were selected for further drug trials. Rotational behavior was determined in automatically recording rotometers, details of which were recently described.30 Groups of four to eight rats were injected sc with the test compounds and then placed immediately into the rotometer. Rotational behavior was continuously recorded until its cessation. The results are expressed as total number of t,urns. Acknowledgment. The authors express their appreciation to Dr. G. Shilling and his associates for microanalytical and spectral data. The skillful assistance of M. Asselin and J. Csakvary in the chemical synthesis and N. Lapeyre and Ida Vozzella in the pharmacological studies is gratefully acknowledged.
Drug Testing and Analysis, Jun 6, 2016
Lysergic N,N-diethylamide (LSD) is perhaps one of the most intriguing psychoactive substances kno... more Lysergic N,N-diethylamide (LSD) is perhaps one of the most intriguing psychoactive substances known and numerous analogs have been explored to a varying extent in previous decades. In 2013, N 6-allyl-6-norlysergic acid diethylamide (AL-LAD) and (2'S,4'S)-lysergic acid 2,4dimethylazetidide (LSZ) have appeared on the 'research chemicals' / new psychoactive substances (NPS) market in both powdered and blotter form. This study reports the analytical characterization of powdered AL-LAD and LSZ tartrate samples and their semi-quantitative determination on blotter paper. Included in this study was the use of nuclear magnetic resonance spectroscopy, gas chromatography mass spectrometry (MS), low and high-resolution electrospray MS(/MS), high performance liquid chromatography diode array detection and GC solid-state infrared analysis. One feature shared by serotonergic psychedelics, such as LSD, is the ability to mediate behavioral responses via activation of 5-HT 2A receptors. Both AL-LAD and LSZ displayed LSD-like responses in male C57BL/6J mice when employing the head-twitch response (HTR) assay. AL-LAD and LSZ produced nearly identical inverted-U-shaped dose-dependent effects, with the
Journal of Psychopharmacology, 2019
Background: In the past few years, the issue of ‘microdosing’ psychedelics has been openly discus... more Background: In the past few years, the issue of ‘microdosing’ psychedelics has been openly discussed in the public arena where claims have been made about their positive effect on mood state and cognitive processes such as concentration. However, there are very few scientific studies that have specifically addressed this issue, and there is no agreed scientific consensus on what microdosing is. Aim: This critique paper is designed to address questions that need to be answered by future scientific studies and to offer guidelines for these studies. Approach: Owing to its proximity for a possible approval in clinical use and short-lasting pharmacokinetics, our focus is predominantly on psilocybin. Psilocybin is allegedly, next to lysergic acid diethylamide (LSD), one of the two most frequently used psychedelics to microdose. Where relevant and available, data for other psychedelic drugs are also mentioned. Conclusion: It is concluded that while most anecdotal reports focus on the posit...
Proceedings of the National Academy of Sciences of the United States of America, Jan 11, 2016
Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the hum... more Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD's marked effects on the visual cortex did not significantly correlate with the drug's other characteristic e...
Arkivoc, 2011
To assess the importance of conformation and placement of the β-substituent of agonist ligands ta... more To assess the importance of conformation and placement of the β-substituent of agonist ligands targeted to the D 1 dopamine receptor, (±)-trans-6,6a,7,8,13,13a-hexahydrobenzo[e]chromeno [3,4-b]azepine-2,3-diol 5 and (±)-trans-6,6a,7,8,9,13b-hexahydrobenzo[d]chromeno[3,4b]azepine-2,3-diol 6 were synthesized as ring-expanded analogues of the high affinity D 1 dopamine receptor selective agonist doxanthrine, using a novel tetrahydrobenzazepine ringforming strategy. Compounds 5 and 6 had only micromolar affinity at the D 1 receptor. Molecular modeling show deviations in the orientation of the accessory phenyl ring between 4 and its ring expanded analogs 5 and 6. Furthermore, the additional methylene group in the azepine ring may cause an unfavorable steric intrusion into the receptor binding process. These conformational differences suggest that the placement of the accessory phenyl ring must be well defined.
Beilstein Journal of Organic Chemistry, 2012
A strategy to replace the ethylamine side chain of 2,5-dimethoxy-4-iodoamphetamine (DOI, 1a), and... more A strategy to replace the ethylamine side chain of 2,5-dimethoxy-4-iodoamphetamine (DOI, 1a), and 2,5-dimethoxy-4-bromoamphetamine (DOB, 1b) with a cyclopropylamine moiety was successful in leading to compounds with high affinity at the 5-HT2 family of receptors; and the more potent stereoisomer of the cyclopropane analogues had the expected (−)-(1R,2S)-configuration. Screening for affinity at various serotonin receptor subtypes, however, revealed that the cyclopropane congeners also had increased affinity at several sites in addition to the 5-HT2A and 5-HT2B receptors. Therefore, at appropriate doses – although (−)-4 and (−)-5 may be useful as tools to probe 5-HT2 receptor function – one would need to be mindful that their selectivity for 5-HT2A receptors is somewhat less than for DOI itself.
Journal of Pharmaceutical Sciences, 1971
IJ Various ring-methoxylated 1-phenyl-2-propanols and 1-phenyl-2-propanones were synthesized and ... more IJ Various ring-methoxylated 1-phenyl-2-propanols and 1-phenyl-2-propanones were synthesized and pharmacologically evaluated. Most compounds had depressantlike activity. The ketones were readily reduced by rabbit liver microsomes. No reductase activity was found in rat and mouse liver preparations. Partition coefficients were determined, and a linear correlation between LRA6,'s (loss of righting ability in 50% of the mice) and partition coefficients was observed for six of the compounds investigated. Keyphrases 0 1-Phenyl-2-propanols, 1-phenyl-2-propanones,
Journal of Medicinal Chemistry, 2006
Synthesis, 2009
An efficient synthesis of the dopamine D 1 selective full agonist dihydrexidine has been achieved... more An efficient synthesis of the dopamine D 1 selective full agonist dihydrexidine has been achieved in high yields and requiring no chromatographic separations via a facilitated intramolecular Henry cyclization of a (nitropropyl)benzophenone and subsequent diastereomerically selective reduction of the resulting tricyclic nitroalkene.
Molecular pharmacology, 2012
To refine further the structure-activity relationships of D(1) dopamine receptor agonists, we inv... more To refine further the structure-activity relationships of D(1) dopamine receptor agonists, we investigated the roles of three conserved serine residues [Ser198(5.42), Ser199(5.43), and Ser202(5.46)] in agonist binding and receptor activation. These transmembrane domain 5 (TM5) residues are believed to engage catechol ligands through polar interactions. We stably expressed wild-type or mutant (S198A, S199A, and S202A) D(1) receptors in human embryonic kidney cells. These receptors were expressed at similar levels (approximately 2000 fmol/mg) and bound the radioligand [(3)H]R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390), although S198A and S199A displayed significant losses of affinity compared with that for wild-type receptors. The endogenous agonist, dopamine, had losses of potency at each of the mutant receptors. We tested cyclohexyl-substituted isochroman, carbocyclic, and chroman bicyclic dopamine analogs and found that the mutations aff...
ChemInform, 2010
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
NIDA research monograph, 1978
Psychopharmacology, 1993
Fenfluramine, a phenalkylamine with serotonin (5-HT) releasing properties, decreases motor activi... more Fenfluramine, a phenalkylamine with serotonin (5-HT) releasing properties, decreases motor activity in rats. The following studies assessed the contribution of 5-HT release to the behavioral effects of fenfluramine and norfenfluramine using a behavioral pattern monitor that simultaneously assesses locomotor and investigatory behavior. First, both fenfluramine and its active metabolite d-norfenfluramine dose-dependently reduced locomotor and investigatory activity. The norfenfluramine-induced reduction in activity was not antagonized by pretreatment with the 5-HT uptake inhibitor fluoxetine or the 5-HT synthesis inhibitor p-chlorophenylalanine, drugs that reduce drug-induced 5-HT release. Second, the d-and/-enantiomers of norfenfluramine were nearly equipotent at reducing behavioral activity, although d-norfenfluramine is more potent as a 5-HT releasing agent. Third, p-chloroamphetamine, a drug that shares the 5-HT releasing properties of fenfluramine produced locomotor hyperactivity in the same paradigm. Previous studies indicate that other 5-HT releasing phenalkylamines have behavioral effects resembling those of p-chloroamphetamine rather than those of fenfluramine. Finally, a structurally related drug, 4-methoxy-5-methyl-aminoindan (MMAI), produced dose-dependent reductions in behavioral activity that are similar to the effects of fenfluramine. The behavioral effects of MMAI were not antagonized by fluoxetine or by the 5-HT receptor antagonist methiothepin. These data suggest that the decrease in activity induced by fenfluramine, norfenfluramine and the related drug MMAI is not related to 5-HT release.
Psychopharmacology, 2012
RATIONALE-Ayahuasca is a psychoactive tea prepared from a combination of plants that contain a ha... more RATIONALE-Ayahuasca is a psychoactive tea prepared from a combination of plants that contain a hallucinogenic tryptamine and monoamine oxidase inhibitors (MAOIs). Behavioral Pattern Monitor (BPM) experiments demonstrated that the combination of 5-methoxy-N,Ndimethyltryptamine (5-MeO-DMT) and a behaviorally inactive dose of an MAO A inhibitor such as harmaline or clorgyline induces biphasic effects on locomotor activity in rats, initially reducing locomotion and then increasing activity as time progresses. OBJECTIVES-The present study investigated whether the biphasic locomotor profile induced by the combination of 5-MeO-DMT and an MAOI is a consequence of a reduction in the rate of 5-MeO-DMT metabolism. This hypothesis was tested using a deuterated derivative of 5-MeO-DMT (, , ,-tetradeutero-5-MeO-DMT) that is resistant to metabolism by MAO. RESULTS-Confirming our previous findings, 1.0 mg/kg 5-MeO-DMT (s.c.) had biphasic effects on locomotor activity in rats pretreated with a behaviorally inactive dose of the nonselective MAOI pargyline (10 mg/kg). Administration of 5-MeO-DMT alone, even at doses greater than 1.0 mg/kg, produced only reductions in locomotor activity. Although low doses of , , ,-tetradeutero-5-MeO-DMT (0.3 and 1.0 mg/kg, s.c.) produced only hypoactivity in the BPM, a dose of 3.0 mg/kg induced a biphasic locomotor profile similar to that produced by the combination of 5-MeO-DMT and an MAOI. Receptor binding studies demonstrated that deuterium substitution had little effect on the affinity of 5-MeO-DMT for a wide variety of neurotransmitter binding sites. CONCLUSIONS-The finding with , , ,-tetradeutero-5-MeO-DMT indicates that the hyperactivity induced by 5-MeO-DMT after MAO inhibition is a consequence of reduced metabolism of 5-MeO-DMT, leading to prolonged occupation of central serotonin receptors. These results demonstrate that deuterated tryptamines may be useful in behavioral and pharmacological studies to mimic the effects of tryptamine/MAOI combinations.
Psychopharmacology, 2012
Rationale Preclinical evidence indicates that D 1 dopamine receptor full agonists have potential ... more Rationale Preclinical evidence indicates that D 1 dopamine receptor full agonists have potential as therapeutic agents for a variety of neurological conditions. Dihydrexidine (DHX) was the first high potency selective D 1 dopamine receptor full agonist and has been studied as a possible treatment for Parkinson's disease (PD). Recently, we discovered doxanthrine (DOX), an oxygen bioisostere of DHX that has even greater selectivity for the D 1 dopamine receptor. Objectives Using the unilateral 6-hydroxydopamine-lesioned rat model of PD, DOX and DHX were compared at several doses (0.625, 1.25, 2.5, or 5.0 mg/kg) for their ability to elicit contralateral rotation by either intraperitoneal injection or oral gavage. Results After intraperitoneal administration, both DOX and DHX showed robust contralateral rotation at doses of 2.5 and 5.0 mg/kg compared to vehicle. In addition, after intraperitoneal administration at doses of 2.5 and 5.0 mg/kg, DHX had a significantly longer duration of action than DOX (p<0.05). Areas under the curves (AUC) for DOX and DHX were not significantly different, however, indicating that DOX and DHX have similar potency after intraperitoneal administration. By contrast, after oral administration, 2.5 and 5.0 mg/kg of DOX produced significant contralateral rotations (p<0.05), whereas DHX showed no significant activity after oral administration of any dose. Conclusion These results demonstrate that although DHX and DOX have similar activity after intraperitoneal administration, DOX demonstrated greater activity after oral administration compared to DHX. Despite its catechol functionality, DOX may possess sufficient oral availability for development as a human therapeutic agent.
Pharmacology Biochemistry and Behavior, 1989
transiently alters biogenic amines and metabolites in mouse brain and heart. PHARMACOL BIOCHEM BE... more transiently alters biogenic amines and metabolites in mouse brain and heart. PHARMACOL BIOCHEM BEHAV 34(2) 223-227, 1989.-(-'-)-3,4-Methylenedioxymethamphetamine (MDMA) (10, 20, and 40 mg/kg) was administered to male CF-1 mice which were sacrificed 3, 6, or 24 hours posttreatment for analysis of brain and cardiac biogenic amines and metabolites. In contrast to reported effects of MDMA in the rat, the highest dose of MDMA transiently elevated mouse brain 5-hydroxytryptamine (5-HT) 3 hours following drug treatment. Levels of dopamine were not significantly affected. 5-Hydroxyindoleacetic acid and dihydroxyphenylacetic acid were significantly lowered by MDMA at the two early time points. The highest dose of MDMA produced a transient depletion of norepinephrine in mouse brain and heart tissue. Only the effects of MDMA on cardiac norepinephrine were prevented by pretreatment of animals with desipramine. A regimen consisting of four daily doses of 40 mg/kg MDMA only produced significant declines in 5-HIAA, dopamine and homovanillic acid levels one week following the last dose. These data confirm previous reports that mice are resistant to the neurotoxic effects of MDMA suggesting that a species variation in response to MDMA exists. MDMA Biogenic amines Neurotoxicity
Neuropsychopharmacology, 1994
Robust individual differences in social behavior have been ob tained by selectively breeding Inst... more Robust individual differences in social behavior have been ob tained by selectively breeding Institute for Cancer Research mice for high and low levels of aggression. As previously shown, when paired with a non-selected, group-housed partner mouse, NC900 mice exhibit isolation-induced aggression. Conversely, NClDO mice fail to attack, freezing upon social contact. Previous studies have established that NClDO mice have lower dopamine concentrations in nucleus accumbens and caudate nucleus, with increased dopamine receptor densities in these same regions. Thus, we wished to determine the effect of administration of a dopamine receptor agonist on social behavior. Mice of both lines were administered 0, 1, 3, or lD mglkg (SC) of the full efficacy Dl receptor agonist dihydrexidine, and their behavior was assessed in a social interaction test.
Nature Reviews Neuroscience, 2013
Life Sciences, 1978
The hallucinogen analog tram-2-(2,5-dimethoxy-4-methylphenyl)-cyclopropylamiae (DMCPA) was resolv... more The hallucinogen analog tram-2-(2,5-dimethoxy-4-methylphenyl)-cyclopropylamiae (DMCPA) was resolved into its two optical isomers. Eaaminatioa of selected behavioral, profiles in mice and cats clearly showed that the levorotatory isomer of DMCPA possesses atereoaelective activity when compared with the dextro isomer. The results parallel those obtained using the isomers of the known hallucinogen, DOM (STP) in the same animal models. Comparison of the optical rotatory dispersion (ORD) curves for the N-(5-bromosalicylidene) derivatives of DMCPA and traps-2pheaylcyclopropylamine (tranylcypromlne) of known absolute configuration established the configuration of DMCPA to be (-)-1R,2S. This stereoselective activity and proof of absolute configuration lend strong support to a new model of the hallucinogen receptor. The proposed model suggests possible structural similarities between LSD and phenethylamine hallucinogens. Recently we proposed a new way to view the possible structural relationship between LSD and hallucinogens of the phenethylamine class such as mescaline or DOM (STP) (1). We used our hypothesis to predict that the active enantiomer of rigid tram-2-phenylcyclopropylamine hallucinogens would possess the 1R,2S absolute configuration (e .g. figure 2c). We now report data which confirm this prediction and lend support to our view of the hallucinogen receptor. Materials and Methode Drugs. The (+) and (-) isomers of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane hydrochloride (DOM) were obtained through the cooperation of the Research Technology Branch, National Institute on Drug Abuse, and had [a]D~-I-17 .1°and-17.7°, respectively. The (+) and (-) isomers of tram-2-(2,5-dimethoxy-4methylphenyl)-cyclopropylamine hydrochloride (DMCPA) were prepared in our laboratories by synthesis and chemical resolution and had [a]Da+55 .2°and-55.6°, respectively. The (+) and (-) isomers of traaylcypromine were donated by Smith, Rline and French Laboratories. Animals. Adult male Swiss-Webeter mice (30-40 g) were obtained from Laboratory Supply Co ., Inc. (Indianapolis, In .) and were housed in groups of ten and