Dark Classics in Chemical Neuroscience: Comprehensive Study on the Biochemical Mechanisms and Clinical Implications of Opioid Analgesics (original) (raw)
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Dark Classics in Chemical Neuroscience C
Chemical Methodologies, 2023
One of the most significant medication families of drugs utilized for intensive treatment, and acute or chronic pain are morphine, opium, and opium-like drugs. The chemical synapse is the place of the effect of drugs and neurotransmitters. Opioids exert their analgesic properties through biochemical changes at chemical synapses by stimulating opioid receptors. Opioids prevent the transmission of pain messages to higher nerve centers by releasing the inhibitory transmitters in the synapse. The problem of using these substances is addiction and severe dependence on them due to the feeling of euphoria, relaxation, and painlessness caused by the use of these substances. Many aspects of the clinical action of opiates are still unknown. Therefore, research on the novel features of these compounds is ongoing in biochemistry and pharmaceutical sciences to synthesize drugs with fewer side effects and more effectiveness. On the other hand, the gate theory is one of the most important theories in controlling pain signals and analgesic drugs. Therefore, comprehensive knowledge and study of analgesic compounds are necessary to achieve the primary goal. Aromatic NH such as in tetrazole and mitragynine, and NH resonance next to the carbonyl functional group like that in carbamates has a high potential to create opioid properties due to the potential of creating tautomeric structures.
Quantum chemical studies of morphine-like opiate narcotics. Effect of N-substituent variations
Journal of Medicinal Chemistry, 1975
Quantum chemical calculations including extensive conformational variations are performed on three morphine-like analgesics with varying N-substituents using the PCILO and INDO methods. The three compounds, morphine, nalorphine, and N -phenethylmorphine, have been shown experimentally to exemplify opiate narcotic agonism, antagonism, and increased agonism, respectively. In this study, these properties are correlated with the electronic and conformational results. The electronic properties of the fused ring skeleton including specifically the cationic region around the nitrogen are relatively unaffected by varying N-substituents. The properties studied include net charges. bond polarities, and the nature and energy of the highest filled and lowest empty molecular orbitals. The conformational behavior appears to he the main cause of differing receptor binding and interaction with the active site and is discussed in these terms.
Novel approaches in the development of new analgesics
Neurophysiologie Clinique/Clinical Neurophysiology, 1990
A recently developed series of highly selective and systemically active g-agonists such as Tyr-X~Gly-Pfie~Letl~Thr(OtBu), with X = D.Ser (OtBu) in BUBU and X = D.Cys(StBu) in BUBUC~ and complete ifihibitors of enkeptmlin metabolism (Kelatorphan, RB 38 A, PC 12) have enabled the major role played by/z-opioid receptors in supraspinal analgesia to be demonstrated• This is in agreement With the~results of in vivo ~t-receptor.~occupancy measured by taking into account the cross-reactivity of the ~-lig~md~. for ~,-sites,.In contrast(# and 3 binding sites seem to act independently to control pain at th~ spinal level. S~rong.anai'gesic effects, especially in arthritic rats, can also be obtained by complete protection of toni-cally~or tplra~gmall~¢ released endogenous enkephalins with mixed inhibitors such as RB38A. Chronic icv • ¢ , administration of tll~t agomst,DAGO, led to a severe naloxone precipitated withdrawal syndrome whilst a weak dependence was seen with the g agonist, DSTBULET or with RB 38 A. Moi-eo~vev;rmi~d.,inhibi'tors did not induce any significant respiratory depression• All these data emphasize the iriterest ink'de-vel6pping~--agonis,l~s,and mixed inhibitors with appropriate biovailability for clinical evaldati0m analgesics / pain R~suml~-'---D~veloppement r~cent d'une nouvelle s~rie d'agonistes opioides, ,Le ddveloppement r~cent d'une nouvellb s~rie d'agonistes opioi'des ~ hautement sdlectifs et actifs par voie ayst~mique te'ts tlue Tyr-X-Gly-Phe-Leu= Thr(OtB~):avec X = D. Ser(OtBu) B UB U et x = D. Cys(StBu) B UBUC,/ainsi que d " une nou velle. sd/ie d'fiihibiteurs complets du mdtabolisme des enkdphdines (k~latorphan, RB 38A., PC 12) a permis de'dd}nontrer l'implication majoritaire des rdcepteurs tz clans l'analgdsie supraspinale. Ceci est e~ ae¢ord avec les expdriences,in vivo d'occupation des sites tz, lorsque l'on prend en compte la:rdaetivit~ eroisde des,ligands~ pou~les sites ~z. Inversement les sites de liaison tt et ~ semblek~t modulds ind~pendamment lg contr~le'de;douleur au niveau spinal. De plus, l'utilisation d'inhibiteurs tel tlRe le RB 384, qui protbgent compldtement~:les enkdphtffines endog~nes libdrdes de fa~on tonique,et'plrasique de la ddgradation enzymatique, conduit d des eff~ts analgdsiques intenses, en particulier chez le rat arthitique.: Une administration chronique~par voie icy de DAGO, un agoniste ~z sdlectif,-suivie;d'une administrationde naldxone; induit un sysdrome de, manctu, e sdvbre, analogue d celui induit par la morphine, alors qu'un effet de ddpendclnce fait~esrob,~ervd avec le DSTBULET ou le RB 38A. Par ailleurs, les inhibiteurs mixtes n'induisent pfts de ddpression respiratoire. Toutes ces donndes ddmontrent l'int~r~t "de d~velopper des agonistes ~et des inhibiteurs mixles prdsentant la biodisponibilitd ndcessaire pour une ~valuation clinique. analgdsique ,/ douleur
The synthesis of novel analgesics based on the morphine prototype
1998
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The influence of esters and carboxylic acids as the N-substituent of opioids. Part 1: Benzomorphans
Bioorganic & Medicinal Chemistry, 2008
To investigate the effects of carboxylic ester and acid moieties as the N-substituent of opioids, a short series of racemic N-substituted normetazocines was prepared. The introduction of both groups as the normetazocine N-substituent produced compounds which displayed low potency in vitro and in vivo, with the esters displaying the greater activity. The pharmacology of the compounds is discussed with implications resulting from potential in vivo metabolic hydrolysis.
Analgesics: New Target and Sources
Pain Relief - From Analgesics to Alternative Therapies, 2017
The aim of this chapter is to describe targets for analgesic drugs, including currently available target sites and possible future target sites for pain and information regarding analgesia for complete understanding of pain originating mechanism, pathways and related theories to recognize. This chapter fully describes methods for determination of analgesic effects of synthetic and natural substances by inducing pain in different models and methods of pain induction.
Natural and partially synthetic analgesics
Acta Medica Medianae, 2005
Humans have a long history of stimulating and mind-altering substances use. Depressive drugs, including morphine and other narcotics, barbiturates and ethanol, are strongly addictive for susceptible individuals. The phenomenon is most striking in the case of opiates. Morphine is an alkaloid of opium. Named after the Roman god of dreams, Morpheus, the compound has potent analgesic properties toward all types of pain. By supstitution of two hydroxylic groups of morphine many natural and semysyntetic derivatives with different pharmacological activity and analgesic action are obtained. Determinations and quantifications of narcotic analgesics in drug addicts are important in forensic medicine and clinical toxicology. With development of highly sensitive chromatography technique (HPLC-GC, GH-MS), more and more substances are determined, including opioid drugs: morphine, codeine, dyhydrocodeine, and heroin and 6-monoacetyl morphine. Hair analysis by HPLC/MS spectroscopy is an effective f...
1994
Resolved axial (/3) and equatorial (a) forms of S-methyl (/3-sulforphanol, a-sulforphanol) and S-allyl (/3-sulfallorphan, a-sulfallorphan) morphinans were tested for their ability to depress the electrically evoked contractions of the guinea pig ileum and of the mouse vas deferens, to compete with the binding of prototype ligands selective for/z-, ~-, and K-opioid receptors in membrane preparations of rat brain and guinea pig cerebellum and to produce analgesia in a rat thermal pain assay. /3-Sulforphanol was more potent than a-sulforphanol in the guinea pig ileum (relative potencies of 93% and 29% respectively, as compared with levorphanol)./3-Sulfallorphan and a-sulfallorphan were both inactive in the guinea pig ileum assay. In the mouse vas deferens preparation, /3-sulforphanol and a-sulforphanol had relative potencies of 2.1% and 1.2% as compared with levorphanol, respectively, while the S-allyl derivatives were inactive. All morphinan derivatives displayed marked binding selectivity for /~-opioid receptors but a-sulfallorphan also showed significant binding potency on 8-opioid receptors (12% as compared to levorphanol). The compounds were also tested for their ability to antagonize the biological activity of morphine. In the guinea pig ileum, a-sulfallorphan potently inhibited morphine with a K e value of 41.7 nM. a-Sulforphanol also antagonized morphine but with a smaller potency (K e = 350 nM). In the mouse vas deferens, no antagonist activity against morphine was observed with any morphinan derivative tested at 1 p.M. In the rat thermal pain assay,/3-sulforphanol (intracisternally, i.c.) was more potent than a-sulforphanol in producing analgesia while the other morphinan derivatives were inactive. In addition, t~-sulfailorphan displayed potent antagonist activity against the antinociceptive effect of levorphanol and in this respect it was at least 10 times as potent as/3-sulfallorphan. These data indicate that the equatorial conformation of the allyl group in morphinan derivatives confers an antagonist property to the molecule while the agonist activity of sulforphanol greatly depends upon the axial orientation of the methyl group.
European Journal of Pharmacology, 2007
In the search for a selective delta-opioid receptor agonist, (-)-(1R,5R,9R)-5,9-dimethyl-2'hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082) and the (+)enantiomer were synthesized and tested. (-)-NIH 11082 displayed antinociceptive activity in the paraphenylquinone test (PPQ test) in male ICR mice [ED 50 = 1.9 (0.7 -5.3) mg/kg, s.c.] and showed little, if any, activity in the tail-flick and hot-plate assays. The (+)-enantiomer was essentially inactive indicating stereoselectivity. Opioid receptor subtype characterization studies indicated that naltrindole, a delta-opioid receptor antagonist, was potent versus the ED 80 of (-)-NIH 11082 in the PPQ test [AD 50 = 0.75 (0.26 -2.20) mg/kg, s.c]. beta-Funaltrexamine and norbinaltorphimine, selective mu-and kappa-receptor antagonists, respectively, were inactive versus the ED 80 of (-)-NIH 11082. In rats with inflammation-induced pain, (-)-NIH 11082 produced antihyperalgesic effects that were attenuated by naltrindole. In morphine-dependent rhesus monkeys of both sexes, (-)-NIH 11082 neither substituted for morphine nor exacerbated withdrawal signs in the dose range of 4.0 to 32.0 mg/kg, s.c. Neither convulsions nor other overt behavioral signs were observed in any of the species tested. The results indicate that (-)-NIH 11082 has delta-opioid receptor properties.