Stephen Husbands - Academia.edu (original) (raw)
Papers by Stephen Husbands
J Med Chem, 2003
Both dopamine uptake inhibitors and σ 1 receptor antagonists have been implicated as potential ph... more Both dopamine uptake inhibitors and σ 1 receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlying reinforcing properties, σ 1 antagonists have been shown to attenuate some behavioral actions and toxic side effects associated with cocaine overdose. Rimcazole, a σ 1 receptor antagonist that binds to the DAT (K i) 224 nM), is not behaviorally cocaine-like and attenuates some of the behavioral actions of cocaine. To determine the roles of both DAT and σ 1 receptors in the behavioral actions of rimcazole, a series of analogues was synthesized. Initial studies identified two analogues (1 and 4) that showed high to moderate affinities for both DAT and σ 1 receptors and failed to show cocaine-like discriminative stimulus (DS) effects. A second series of bis(4′-fluorophenyl)amine analogues have now been prepared in which the most potent DAT compound, 19 (K i) 8.5 nM), was selective over serotonin transporter (SERT/DAT) 94), norepinephrine transporter (NET/DAT) 63), and σ 1 receptor binding (σ 1 /DAT) 44). In addition, two other analogues 10 and 17 showed superior selectivity for DAT over SERT (170-and 140-fold, respectively) and DAT over NET (219-and 190-fold, respectively) but were essentially equipotent at DAT and σ 1 receptors (10; K i) 77 and 124 nM, respectively, 17; K i) 28 and 13 nM, respectively). CoMFA studies at both DAT and σ 1 receptors were performed to examine structural requirements for optimal binding at these two targets as well as to assess differences between them. Behavioral evaluation of analogues with varying affinities for both DAT and σ 1 receptors may provide a novel approach toward designing medications for cocaine abuse.
Topics in Current Chemistry, 2011
14-Hydroxy-7,8-dihydromorphinone (oxymorphone) and its derivatives (oxycodone, naloxone, naltrexo... more 14-Hydroxy-7,8-dihydromorphinone (oxymorphone) and its derivatives (oxycodone, naloxone, naltrexone) have become among the most important clinical agents to have been produced from opium. 14-Aminocodeinone and its 7,8-dihydro and morphinone derivatives are of more recent origin thanks to the work of Professor Gordon Kirby and his collaborators. The 14-amino parent compounds have proved of limited interest but their 14-acylamino- and 14-alkylamino derivatives have been extensively studied. The 4'-substituted cinnamoylamino-17-cyclopropylmethyl-7,8-dihydronormorphinones, C-CAM and M-CAM are the best available selective MOR irreversible antagonists and the related dihydrocodeinone MC-CAM, 4'-chloro-cinnamoylamino-17-cyclopropylmethyl-7,8-dihydronorcodeinone, is a long-acting MOR partial agonist with extended MOR-pseudoirreversible antagonist activity that could be a candidate for pharmacotherapy of opiate abuse/dependence.
ChemInform, 2001
ABSTRACT The study of κ-opioid receptor function in vivo has been hampered by the limited choice ... more ABSTRACT The study of κ-opioid receptor function in vivo has been hampered by the limited choice of selective κ-antagonists. Recently discovered κ-antagonists have not yet been utilised in vivo. We here report the synthesis and in vitro evaluation of a new amidine derivative of naltrindole. It showed substantially greater κ-selectivity in binding assays than known analogues with shorter spacer in the amidine side chain. This indicates that in nor-BNI and related selective κ-antagonists, the second basic centre may not be ideally located.
Psychopharmacology, 2008
Rationale Previous research has found the stimulus effects of dopamine D2-and D3-preferring agoni... more Rationale Previous research has found the stimulus effects of dopamine D2-and D3-preferring agonists difficult to distinguish in drug discrimination studies. Antagonism studies suggest that the stimulus effects of both types of agonists may be mediated primarily through D2 receptors. Objectives The current study was designed to further assess the receptors mediating the stimulus effects of these agonists and to attempt to train rats to discriminate directly between D2-and D3-preferring dopamine agonists. Materials and methods Four groups of eight rats were trained to discriminate either 0.1 mg/kg of the D3preferring agonist pramipexole from saline, 1.0 mg/kg of the D2-preferring agonist sumanirole from saline, 0.1 mg/kg pramipexole from either saline or 1.0 mg/kg sumanirole, or 1.0 mg/kg sumanirole from either saline or 0.1 mg/kg pramipexole. Results Three of eight rats in the 0.1 mg/kg pramipexole vs. 1.0 mg/kg sumanirole or saline failed to meet the training criteria, and the discrimination in this group was tenuous. The D2-preferring antagonist L-741,626 at 1.0 mg/kg was more effective at shifting to the right the pramipexole dose-response curve in pramipexole-trained rats, while 32 mg/kg of the selective D3 antagonist PG01037 had little effect. Quinpirole and 7-OH-DPAT fully or partially substituted for both pramipexole and sumanirole in each group tested, while cocaine did not substitute in any group. Conclusions Antagonist data along with the pattern of training and substitution data suggested that D2 receptor activation is primarily responsible for the stimulus effects of both sumanirole and pramipexole with D3 receptor activation playing little or no role.
Neuroscience Letters, 2007
Imidazoline-2 binding sites (I 2-BS) are widely distributed in rat brain and our studies have sho... more Imidazoline-2 binding sites (I 2-BS) are widely distributed in rat brain and our studies have shown that drugs selective for these sites regulate central extrasynaptic monoamine concentrations. Radioligand binding studies have recently shown that BU98008 (1-[4,5-dihydro-1H-imidazol-2-yl] isoquinoline) displays high affinity at I 2-binding sites. The aim of this study was set to assess the pharmacological actions of BU98008 in a functional in vivo model using the technique of in vivo brain microdialysis. Systemic injection of 20 mg/kg BU98008 produced an 85% rise in extracellular noradrenaline levels compared with basal values in the rat frontal cortex. Further experiments demonstrated that peripheral administration of 10 and 20 mg/kg BU98008 elicited a transient 25% elevation in dopamine overflow compared with basal values and simultaneously produced an 18% decrease in extracellular DOPAC (3-4-dihydroxyphenylacetic acid) levels compared to basal values. In addition, BU98008 did not appear to affect serotonergic neurotransmission in the frontal cortex. In conclusion, the present study demonstrates that BU98008 shares some functional similarities with known selective I 2-BS ligands.
Molecular Pharmacology, 2010
Journal of Pharmacology and Experimental Therapeutics, 2009
![Research paper thumbnail of A Diastereospecific Synthesis of 2-Methyl-5β-phenyl-5α-carbethoxy-2- azabicyclo[2.2.1]heptane: A Ring-Constrained Analogue of Meperidine](https://attachments.academia-assets.com/104442673/thumbnails/1.jpg)
](The Journal of Organic Chemistry, 1998
Journal of Medicinal Chemistry, 2003
Both dopamine uptake inhibitors and σ 1 receptor antagonists have been implicated as potential ph... more Both dopamine uptake inhibitors and σ 1 receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlying reinforcing properties, σ 1 antagonists have been shown to attenuate some behavioral actions and toxic side effects associated with cocaine overdose. Rimcazole, a σ 1 receptor antagonist that binds to the DAT (K i) 224 nM), is not behaviorally cocaine-like and attenuates some of the behavioral actions of cocaine. To determine the roles of both DAT and σ 1 receptors in the behavioral actions of rimcazole, a series of analogues was synthesized. Initial studies identified two analogues (1 and 4) that showed high to moderate affinities for both DAT and σ 1 receptors and failed to show cocaine-like discriminative stimulus (DS) effects. A second series of bis(4′-fluorophenyl)amine analogues have now been prepared in which the most potent DAT compound, 19 (K i) 8.5 nM), was selective over serotonin transporter (SERT/DAT) 94), norepinephrine transporter (NET/DAT) 63), and σ 1 receptor binding (σ 1 /DAT) 44). In addition, two other analogues 10 and 17 showed superior selectivity for DAT over SERT (170-and 140-fold, respectively) and DAT over NET (219-and 190-fold, respectively) but were essentially equipotent at DAT and σ 1 receptors (10; K i) 77 and 124 nM, respectively, 17; K i) 28 and 13 nM, respectively). CoMFA studies at both DAT and σ 1 receptors were performed to examine structural requirements for optimal binding at these two targets as well as to assess differences between them. Behavioral evaluation of analogues with varying affinities for both DAT and σ 1 receptors may provide a novel approach toward designing medications for cocaine abuse.
![Research paper thumbnail of Design and Synthesis of [(2,3-Dichlorophenyl)piperazin-1-yl]alkylfluorenylcarboxamides as Novel Ligands Selective for the Dopamine D3Receptor Subtype](https://attachments.academia-assets.com/104442679/thumbnails/1.jpg)
](Journal of Medicinal Chemistry, 2001
*: Design and Synthesis of [(2,3-Dichlorophenyl)piperazin-1-yl]alkylfluorenylcarboxamides as Nove... more *: Design and Synthesis of [(2,3-Dichlorophenyl)piperazin-1-yl]alkylfluorenylcarboxamides as Novel Ligands Selective for the Dopamine D 3 Receptor Subtype.
Bioorganic & Medicinal Chemistry Letters, 2000
ÐAn irreversible ligand (7) has been prepared based on the selective I 2 ligand 2-BFI. Compound 7... more ÐAn irreversible ligand (7) has been prepared based on the selective I 2 ligand 2-BFI. Compound 7 displayed high anity and selectivity for I 2-sites and has been shown to irreversibly bind to these sites in rat brain. Compound 7 should, therefore, prove an invaluable tool for the further elucidation of I 2-site function.
ACS Medicinal Chemistry Letters, 2011
A series of modafinil (1) analogues were synthesized wherein (1) para-halo-substitutents were add... more A series of modafinil (1) analogues were synthesized wherein (1) para-halo-substitutents were added to the aryl rings, (2) the sulfoxide function was removed, and (3) the primary amide group was replaced with secondary and tertiary amides and amines to investigate the effects of these chemical modifications on dopamine transporter, serotonin transporter, and norepinephrine transporter binding. In addition, the locomotor-stimulant effects in mice of (()modafinil (1), its Rand S-enantiomers, and its para-chloro sulfinylacetamide analogue (5c) were compared to those of cocaine.
Chemistry & Biodiversity, 2007
The clerodane diterpenoid salvinorin A (1), the main active component of the psychotropic herb Sa... more The clerodane diterpenoid salvinorin A (1), the main active component of the psychotropic herb Salvia divinorum, has been reported to be a potent agonist at the k-opioid receptor. Computer modeling suggested that splendidin (2) from S. splendens, as well as related compounds, might possess similar activities. In the present study, this hypothesis was tested by determination of the binding properties of a series of structural congeners, compounds 2-8, at the m-, d-, and k-opioid receptors. However, none of these compounds showed significant binding to any of the opioid-receptor subtypes, thus disproving the above hypothesis. The novel compounds 7 and 8 were obtained semi-synthetically by selective modification of salvifarin (5), isolated from Salvia farinacea, upon epoxide-ring opening with AcOH in the presence of indium(III) triflate. Also, the X-ray crystal structure of salvifaricin (6; Fig.), obtained from S. farinacea, was determined for the first time and used, in combination with in-depth NMR experiments, to elucidate the absolute configurations of the new products. Our experiments demonstrate that the relatively wellaccessible diterpenoid 6 could be used as starting material for future studies into the structure-activity relationship at the k-opioid receptor.
Journal of Pharmacology and Experimental Therapeutics, 2019
Disclosure/conflict of interest: BB and PF were employed by Orexigen Therapeutics while engaged i... more Disclosure/conflict of interest: BB and PF were employed by Orexigen Therapeutics while engaged in this research project. SMH is an inventor on the patent that describes OREX-1019/BU10119 and was a consultant to Orexigen Therapeutics during this project.
British journal of pharmacology, Jan 26, 2018
PZM21 is a novel μ-opioid receptor ligand that has been reported to induce minimal arrestin recru... more PZM21 is a novel μ-opioid receptor ligand that has been reported to induce minimal arrestin recruitment and be devoid of the respiratory depressant effects characteristic of classical μ receptor ligands such as morphine. We have re-examined the signalling profile of PZM21 and its ability to depress respiration. G protein (G ) activation and arrestin-3 translocation were measured in vitro, using BRET assays, in HEK 293 cells expressing μ receptors. Respiration (rate and tidal volume) was measured in awake, freely moving mice by whole-body plethysmography, and antinociception was measured by the hot plate test. PZM21 (10 - 3 × 10 M) produced concentration-dependent G activation and arrestin-3 translocation. Comparison with responses evoked by morphine and DAMGO revealed that PZM21 was a low efficacy agonist in both signalling assays. PZM21 (10-80 mg·kg ) depressed respiration in a dose-dependent manner. The respiratory depression was due to a decrease in the rate of breathing not a d...
European journal of pharmacology, Jan 21, 2015
Endogenous opioid and nociceptin systems are widely distributed in the gastrointestinal tract whe... more Endogenous opioid and nociceptin systems are widely distributed in the gastrointestinal tract where they seem to play a crucial role in maintaining homeostasis. The aim of our study was to assess whether activation of nociceptin (NOP) and µ-opioid (MOP) receptors by a mixed NOP/MOP receptor agonist, BU08070, induces anti-inflammatory response in experimental colitis. The anti-inflammatory effect of BU08070 (1mg/kg i.p.) was characterized in the mouse model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis, based on the assessment of the macroscopic and microscopic total damage scores and determination of MPO activity and TNF-α level in the colon. The effect of BU08070 on cell viability and NF-κB was characterized in THP-1 Blue cell line. The antinociceptive activity of BU08070 was examined in mustard oil-induced mouse model of abdominal pain. A potent anti-inflammatory effect of BU08070 (1mg/kg i.p.) was observed as indicated by decrease in macroscopic damage score (1.88±...
Molecular pharmacology, Jan 26, 2015
There is ongoing debate about the role of G protein receptor kinases (GRKs) in agonist-induced de... more There is ongoing debate about the role of G protein receptor kinases (GRKs) in agonist-induced desensitization of the μ opioid receptor (MOPr) in brain neurons (see Williams et al., 2013, Pharmacol Rev 15;223-254). In the present paper we have used a novel, membrane permeable, small molecule inhibitor of GRK2 and GRK3, Takeda Compound 101 (Cmpd101), to study the involvement of GRK2/3 in acute agonist-induced MOPr desensitization. We observed that Cmpd101 inhibits the desensitization of the G protein activated potassium current (GIRK) evoked by receptor- saturating concentrations of methionine enkephalin (Met Enk), D-Ala2,N-MePhe4,Gly-ol]-enkephalin (DAMGO), endomorphin-2 and morphine in rat and mouse locus coeruleus (LC) neurons. In LC neurons from GRK3 knockout mice Met Enk-induced desensitization was unaffected implying a role for GRK2 in MOPr desensitization. Quantitative analysis of the loss of functional MOPrs following acute agonist exposure revealed that Cmpd101 only partiall...
Journal of psychopharmacology (Oxford, England), Jan 4, 2015
Opiates have been used historically for the treatment of depression. Renewed interest in the use ... more Opiates have been used historically for the treatment of depression. Renewed interest in the use of opiates as antidepressants has focused on the development of kappa opioid receptor (κ-receptor) antagonists. Buprenorphine acts as a partial µ-opioid receptor agonist and a κ-receptor antagonist. By combining buprenorphine with the opioid antagonist naltrexone, the activation of µ-opioid receptors will be reduced and the κ-antagonist properties enhanced. We have established that a combination dose of buprenorphine (1 mg/kg) with naltrexone (1 mg/kg) functions as a short-acting κ-antagonist in the mouse tail withdrawal test. Furthermore, this dose combination is neither rewarding nor aversive in the conditioned place preference paradigm, and is without significant locomotor effects. We have shown for the first time that systemic co-administration of buprenorphine (1 mg/kg) with naltrexone (1 mg/kg) in CD-1 mice produced an antidepressant-like response in behaviours in both the forced s...
J Med Chem, 2003
Both dopamine uptake inhibitors and σ 1 receptor antagonists have been implicated as potential ph... more Both dopamine uptake inhibitors and σ 1 receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlying reinforcing properties, σ 1 antagonists have been shown to attenuate some behavioral actions and toxic side effects associated with cocaine overdose. Rimcazole, a σ 1 receptor antagonist that binds to the DAT (K i) 224 nM), is not behaviorally cocaine-like and attenuates some of the behavioral actions of cocaine. To determine the roles of both DAT and σ 1 receptors in the behavioral actions of rimcazole, a series of analogues was synthesized. Initial studies identified two analogues (1 and 4) that showed high to moderate affinities for both DAT and σ 1 receptors and failed to show cocaine-like discriminative stimulus (DS) effects. A second series of bis(4′-fluorophenyl)amine analogues have now been prepared in which the most potent DAT compound, 19 (K i) 8.5 nM), was selective over serotonin transporter (SERT/DAT) 94), norepinephrine transporter (NET/DAT) 63), and σ 1 receptor binding (σ 1 /DAT) 44). In addition, two other analogues 10 and 17 showed superior selectivity for DAT over SERT (170-and 140-fold, respectively) and DAT over NET (219-and 190-fold, respectively) but were essentially equipotent at DAT and σ 1 receptors (10; K i) 77 and 124 nM, respectively, 17; K i) 28 and 13 nM, respectively). CoMFA studies at both DAT and σ 1 receptors were performed to examine structural requirements for optimal binding at these two targets as well as to assess differences between them. Behavioral evaluation of analogues with varying affinities for both DAT and σ 1 receptors may provide a novel approach toward designing medications for cocaine abuse.
Topics in Current Chemistry, 2011
14-Hydroxy-7,8-dihydromorphinone (oxymorphone) and its derivatives (oxycodone, naloxone, naltrexo... more 14-Hydroxy-7,8-dihydromorphinone (oxymorphone) and its derivatives (oxycodone, naloxone, naltrexone) have become among the most important clinical agents to have been produced from opium. 14-Aminocodeinone and its 7,8-dihydro and morphinone derivatives are of more recent origin thanks to the work of Professor Gordon Kirby and his collaborators. The 14-amino parent compounds have proved of limited interest but their 14-acylamino- and 14-alkylamino derivatives have been extensively studied. The 4'-substituted cinnamoylamino-17-cyclopropylmethyl-7,8-dihydronormorphinones, C-CAM and M-CAM are the best available selective MOR irreversible antagonists and the related dihydrocodeinone MC-CAM, 4'-chloro-cinnamoylamino-17-cyclopropylmethyl-7,8-dihydronorcodeinone, is a long-acting MOR partial agonist with extended MOR-pseudoirreversible antagonist activity that could be a candidate for pharmacotherapy of opiate abuse/dependence.
ChemInform, 2001
ABSTRACT The study of κ-opioid receptor function in vivo has been hampered by the limited choice ... more ABSTRACT The study of κ-opioid receptor function in vivo has been hampered by the limited choice of selective κ-antagonists. Recently discovered κ-antagonists have not yet been utilised in vivo. We here report the synthesis and in vitro evaluation of a new amidine derivative of naltrindole. It showed substantially greater κ-selectivity in binding assays than known analogues with shorter spacer in the amidine side chain. This indicates that in nor-BNI and related selective κ-antagonists, the second basic centre may not be ideally located.
Psychopharmacology, 2008
Rationale Previous research has found the stimulus effects of dopamine D2-and D3-preferring agoni... more Rationale Previous research has found the stimulus effects of dopamine D2-and D3-preferring agonists difficult to distinguish in drug discrimination studies. Antagonism studies suggest that the stimulus effects of both types of agonists may be mediated primarily through D2 receptors. Objectives The current study was designed to further assess the receptors mediating the stimulus effects of these agonists and to attempt to train rats to discriminate directly between D2-and D3-preferring dopamine agonists. Materials and methods Four groups of eight rats were trained to discriminate either 0.1 mg/kg of the D3preferring agonist pramipexole from saline, 1.0 mg/kg of the D2-preferring agonist sumanirole from saline, 0.1 mg/kg pramipexole from either saline or 1.0 mg/kg sumanirole, or 1.0 mg/kg sumanirole from either saline or 0.1 mg/kg pramipexole. Results Three of eight rats in the 0.1 mg/kg pramipexole vs. 1.0 mg/kg sumanirole or saline failed to meet the training criteria, and the discrimination in this group was tenuous. The D2-preferring antagonist L-741,626 at 1.0 mg/kg was more effective at shifting to the right the pramipexole dose-response curve in pramipexole-trained rats, while 32 mg/kg of the selective D3 antagonist PG01037 had little effect. Quinpirole and 7-OH-DPAT fully or partially substituted for both pramipexole and sumanirole in each group tested, while cocaine did not substitute in any group. Conclusions Antagonist data along with the pattern of training and substitution data suggested that D2 receptor activation is primarily responsible for the stimulus effects of both sumanirole and pramipexole with D3 receptor activation playing little or no role.
Neuroscience Letters, 2007
Imidazoline-2 binding sites (I 2-BS) are widely distributed in rat brain and our studies have sho... more Imidazoline-2 binding sites (I 2-BS) are widely distributed in rat brain and our studies have shown that drugs selective for these sites regulate central extrasynaptic monoamine concentrations. Radioligand binding studies have recently shown that BU98008 (1-[4,5-dihydro-1H-imidazol-2-yl] isoquinoline) displays high affinity at I 2-binding sites. The aim of this study was set to assess the pharmacological actions of BU98008 in a functional in vivo model using the technique of in vivo brain microdialysis. Systemic injection of 20 mg/kg BU98008 produced an 85% rise in extracellular noradrenaline levels compared with basal values in the rat frontal cortex. Further experiments demonstrated that peripheral administration of 10 and 20 mg/kg BU98008 elicited a transient 25% elevation in dopamine overflow compared with basal values and simultaneously produced an 18% decrease in extracellular DOPAC (3-4-dihydroxyphenylacetic acid) levels compared to basal values. In addition, BU98008 did not appear to affect serotonergic neurotransmission in the frontal cortex. In conclusion, the present study demonstrates that BU98008 shares some functional similarities with known selective I 2-BS ligands.
Molecular Pharmacology, 2010
Journal of Pharmacology and Experimental Therapeutics, 2009
The Journal of Organic Chemistry, 1998
Journal of Medicinal Chemistry, 2003
Both dopamine uptake inhibitors and σ 1 receptor antagonists have been implicated as potential ph... more Both dopamine uptake inhibitors and σ 1 receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlying reinforcing properties, σ 1 antagonists have been shown to attenuate some behavioral actions and toxic side effects associated with cocaine overdose. Rimcazole, a σ 1 receptor antagonist that binds to the DAT (K i) 224 nM), is not behaviorally cocaine-like and attenuates some of the behavioral actions of cocaine. To determine the roles of both DAT and σ 1 receptors in the behavioral actions of rimcazole, a series of analogues was synthesized. Initial studies identified two analogues (1 and 4) that showed high to moderate affinities for both DAT and σ 1 receptors and failed to show cocaine-like discriminative stimulus (DS) effects. A second series of bis(4′-fluorophenyl)amine analogues have now been prepared in which the most potent DAT compound, 19 (K i) 8.5 nM), was selective over serotonin transporter (SERT/DAT) 94), norepinephrine transporter (NET/DAT) 63), and σ 1 receptor binding (σ 1 /DAT) 44). In addition, two other analogues 10 and 17 showed superior selectivity for DAT over SERT (170-and 140-fold, respectively) and DAT over NET (219-and 190-fold, respectively) but were essentially equipotent at DAT and σ 1 receptors (10; K i) 77 and 124 nM, respectively, 17; K i) 28 and 13 nM, respectively). CoMFA studies at both DAT and σ 1 receptors were performed to examine structural requirements for optimal binding at these two targets as well as to assess differences between them. Behavioral evaluation of analogues with varying affinities for both DAT and σ 1 receptors may provide a novel approach toward designing medications for cocaine abuse.
Journal of Medicinal Chemistry, 2001
*: Design and Synthesis of [(2,3-Dichlorophenyl)piperazin-1-yl]alkylfluorenylcarboxamides as Nove... more *: Design and Synthesis of [(2,3-Dichlorophenyl)piperazin-1-yl]alkylfluorenylcarboxamides as Novel Ligands Selective for the Dopamine D 3 Receptor Subtype.
Bioorganic & Medicinal Chemistry Letters, 2000
ÐAn irreversible ligand (7) has been prepared based on the selective I 2 ligand 2-BFI. Compound 7... more ÐAn irreversible ligand (7) has been prepared based on the selective I 2 ligand 2-BFI. Compound 7 displayed high anity and selectivity for I 2-sites and has been shown to irreversibly bind to these sites in rat brain. Compound 7 should, therefore, prove an invaluable tool for the further elucidation of I 2-site function.
ACS Medicinal Chemistry Letters, 2011
A series of modafinil (1) analogues were synthesized wherein (1) para-halo-substitutents were add... more A series of modafinil (1) analogues were synthesized wherein (1) para-halo-substitutents were added to the aryl rings, (2) the sulfoxide function was removed, and (3) the primary amide group was replaced with secondary and tertiary amides and amines to investigate the effects of these chemical modifications on dopamine transporter, serotonin transporter, and norepinephrine transporter binding. In addition, the locomotor-stimulant effects in mice of (()modafinil (1), its Rand S-enantiomers, and its para-chloro sulfinylacetamide analogue (5c) were compared to those of cocaine.
Chemistry & Biodiversity, 2007
The clerodane diterpenoid salvinorin A (1), the main active component of the psychotropic herb Sa... more The clerodane diterpenoid salvinorin A (1), the main active component of the psychotropic herb Salvia divinorum, has been reported to be a potent agonist at the k-opioid receptor. Computer modeling suggested that splendidin (2) from S. splendens, as well as related compounds, might possess similar activities. In the present study, this hypothesis was tested by determination of the binding properties of a series of structural congeners, compounds 2-8, at the m-, d-, and k-opioid receptors. However, none of these compounds showed significant binding to any of the opioid-receptor subtypes, thus disproving the above hypothesis. The novel compounds 7 and 8 were obtained semi-synthetically by selective modification of salvifarin (5), isolated from Salvia farinacea, upon epoxide-ring opening with AcOH in the presence of indium(III) triflate. Also, the X-ray crystal structure of salvifaricin (6; Fig.), obtained from S. farinacea, was determined for the first time and used, in combination with in-depth NMR experiments, to elucidate the absolute configurations of the new products. Our experiments demonstrate that the relatively wellaccessible diterpenoid 6 could be used as starting material for future studies into the structure-activity relationship at the k-opioid receptor.
Journal of Pharmacology and Experimental Therapeutics, 2019
Disclosure/conflict of interest: BB and PF were employed by Orexigen Therapeutics while engaged i... more Disclosure/conflict of interest: BB and PF were employed by Orexigen Therapeutics while engaged in this research project. SMH is an inventor on the patent that describes OREX-1019/BU10119 and was a consultant to Orexigen Therapeutics during this project.
British journal of pharmacology, Jan 26, 2018
PZM21 is a novel μ-opioid receptor ligand that has been reported to induce minimal arrestin recru... more PZM21 is a novel μ-opioid receptor ligand that has been reported to induce minimal arrestin recruitment and be devoid of the respiratory depressant effects characteristic of classical μ receptor ligands such as morphine. We have re-examined the signalling profile of PZM21 and its ability to depress respiration. G protein (G ) activation and arrestin-3 translocation were measured in vitro, using BRET assays, in HEK 293 cells expressing μ receptors. Respiration (rate and tidal volume) was measured in awake, freely moving mice by whole-body plethysmography, and antinociception was measured by the hot plate test. PZM21 (10 - 3 × 10 M) produced concentration-dependent G activation and arrestin-3 translocation. Comparison with responses evoked by morphine and DAMGO revealed that PZM21 was a low efficacy agonist in both signalling assays. PZM21 (10-80 mg·kg ) depressed respiration in a dose-dependent manner. The respiratory depression was due to a decrease in the rate of breathing not a d...
European journal of pharmacology, Jan 21, 2015
Endogenous opioid and nociceptin systems are widely distributed in the gastrointestinal tract whe... more Endogenous opioid and nociceptin systems are widely distributed in the gastrointestinal tract where they seem to play a crucial role in maintaining homeostasis. The aim of our study was to assess whether activation of nociceptin (NOP) and µ-opioid (MOP) receptors by a mixed NOP/MOP receptor agonist, BU08070, induces anti-inflammatory response in experimental colitis. The anti-inflammatory effect of BU08070 (1mg/kg i.p.) was characterized in the mouse model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis, based on the assessment of the macroscopic and microscopic total damage scores and determination of MPO activity and TNF-α level in the colon. The effect of BU08070 on cell viability and NF-κB was characterized in THP-1 Blue cell line. The antinociceptive activity of BU08070 was examined in mustard oil-induced mouse model of abdominal pain. A potent anti-inflammatory effect of BU08070 (1mg/kg i.p.) was observed as indicated by decrease in macroscopic damage score (1.88±...
Molecular pharmacology, Jan 26, 2015
There is ongoing debate about the role of G protein receptor kinases (GRKs) in agonist-induced de... more There is ongoing debate about the role of G protein receptor kinases (GRKs) in agonist-induced desensitization of the μ opioid receptor (MOPr) in brain neurons (see Williams et al., 2013, Pharmacol Rev 15;223-254). In the present paper we have used a novel, membrane permeable, small molecule inhibitor of GRK2 and GRK3, Takeda Compound 101 (Cmpd101), to study the involvement of GRK2/3 in acute agonist-induced MOPr desensitization. We observed that Cmpd101 inhibits the desensitization of the G protein activated potassium current (GIRK) evoked by receptor- saturating concentrations of methionine enkephalin (Met Enk), D-Ala2,N-MePhe4,Gly-ol]-enkephalin (DAMGO), endomorphin-2 and morphine in rat and mouse locus coeruleus (LC) neurons. In LC neurons from GRK3 knockout mice Met Enk-induced desensitization was unaffected implying a role for GRK2 in MOPr desensitization. Quantitative analysis of the loss of functional MOPrs following acute agonist exposure revealed that Cmpd101 only partiall...
Journal of psychopharmacology (Oxford, England), Jan 4, 2015
Opiates have been used historically for the treatment of depression. Renewed interest in the use ... more Opiates have been used historically for the treatment of depression. Renewed interest in the use of opiates as antidepressants has focused on the development of kappa opioid receptor (κ-receptor) antagonists. Buprenorphine acts as a partial µ-opioid receptor agonist and a κ-receptor antagonist. By combining buprenorphine with the opioid antagonist naltrexone, the activation of µ-opioid receptors will be reduced and the κ-antagonist properties enhanced. We have established that a combination dose of buprenorphine (1 mg/kg) with naltrexone (1 mg/kg) functions as a short-acting κ-antagonist in the mouse tail withdrawal test. Furthermore, this dose combination is neither rewarding nor aversive in the conditioned place preference paradigm, and is without significant locomotor effects. We have shown for the first time that systemic co-administration of buprenorphine (1 mg/kg) with naltrexone (1 mg/kg) in CD-1 mice produced an antidepressant-like response in behaviours in both the forced s...