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Biomedical subjects

L S Melvin

Publications and source records attributed to L S Melvin.

27 records · Page 2Linked to original sources
PubMed1988

Nonclassical cannabinoid analgetics inhibit adenylate cyclase: development of a cannabinoid receptor model.

Extensive structure-activity relationship studies have demonstrated that specific requirements within the cannabinoid structure are necessary to produce potent analgesia. A three-point association between the agonist and the receptor mediating analgesia consists of: 1) the C ring hydroxyl, 2) the phenolic A ring hydroxyl, and 3) the A ring alkyl hydrophobic side chain. Potent tricyclic and bicyclic structures were synthesized as "nonclassical" cannabinoid analgetics that conform to this agonist-receptor three-point interaction model. At the cellular level, centrally active cannabinoid drugs inhibit adenylate cyclase activity in a neuroblastoma cell line. The structure-activity relationship profile for inhibition of adenylate cyclase in vitro was consistent with this same three-point association of agonists with the receptor. A correlation exists between the potency of drugs to produce analgesia in vivo and to inhibit adenylate cyclase in vitro. Enantio- and stereoselectivity were exhibited by the nonclassical cannabinoid compounds for both the analgetic response and the ability to inhibit adenylate cyclase. The magnitude of the enantioselective response was equal for both the biochemical and physiological endpoints. Based on the parallels in structure-activity relationships and the enantioselective effects, it is postulated that the receptor that is associated with the regulation of adenylate cyclase in vitro may be the same receptor as that mediating analgesia in vivo. A conceptualization of the cannabinoid analgetic receptor is presented.

Adenylyl Cyclase Inhibitors↗
PubMed1985

Enhancement of brain [3H]flunitrazepam binding and analgesic activity of synthetic cannabimimetics.

Novel, synthetic cannabimimetics and delta 9-tetrahydrocannabinol were found to enhance the binding of [3H]flunitrazepam to mouse brain in vivo. This property, suggestive of facilitation of binding to benzodiazepine receptors, is consistent with the potentiation of the anticonvulsant activity of diazepam against pentylenetetrazol by these compounds. The relative potencies of delta 9-tetrahydrocannabinol and the new cannabimimetics for enhancing [3H]flunitrazepam binding in vivo could also be correlated with their relative analgesic efficacies. Similar pharmacological stereospecificity was displayed for both binding enhancement and analgesic effects. The following order of decreasing potency was observed: N-methyllevonantradol and (-)-CP-55,244 greater than levonantradol, canbisol, CP-42,096 and (-)-CP-55,940 greater than 9-beta-normethyl-9-beta-hydroxyhexahydrocannabinol, nabilone and CP-47,497 greater than delta 9-tetrahydrocannabinol. Dextronantradol, (+)-CP-55,940 and (+)-CP-55,244 were considerably less active than the respective (-)-enantiomers; cannabidiol was inactive. Extensive investigation of structure versus activity led to N-methyllevonantradol and the 3-(2-hydroxyphenyl)cyclohexanols derivative, (-)-CP-55,244, which are approximately 1000-fold more potent than delta 9-tetrahydrocannabinol.

Analgesics↗
PubMed1984

A cannabinoid derived prototypical analgesic.

The synthesis and analgesic testing of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]cyclohexanol (1) are described. Prior (SAR) studies led us to conclude that the pyran ring of 9-nor-9 beta-hydroxyhexahydrocannabinol (HHC) was not necessary for the expression of biological activity in this series of cannabinoids. Analysis of models and the use of molecular mechanics calculations suggested that a simpler compound, such as 1, would possess the biological activity of HHC. Compound 1 was prepared in nine steps from [3-(benzyloxy)phenyl]acetonitrile (2). Biological testing in five models of pain shows that compound 1 and morphine are equally potent as analgesics and demonstrates that the pyran ring of HHC is not necessary for biological activity. Further simplification of 1 was pursued by the synthesis of 4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-pentanol (17), but this derivative exhibits significantly reduced analgesic activity.

Analgesics↗
PubMed1982

Cannabimimetic activity from CP-47,497, a derivative of 3-phenylcyclohexanol.

CP-47,497 (cis-3-[2-hydroxy-4(1,1-dimethylheptyl)phenyl]-cyclohexan-1-ol) is characterized as a cannabimimetic agent, with 3 to 28 times greater potency than delta 9-tetrahydrocannabinol delta 9-THC), based on the following. In common with delta 9-THC and other active structures closely related chemically to delta 9-THC, CP-47,497 exerts analgesic, motor depressant, anticonvulsant and hypothermic effects. It elicits vocalization in palpated rats and ataxia in dogs. In drug discrimination studies in rats, the stimulus properties of delta 9-THC (3.2 mg/kg i.p.) are generalized to CP-47,497, with an absolute threshold dose 3 to 14 times lower than the threshold dose of delta 9-THC itself, depending on route. Furthermore, rats are unable to discriminate between the stimulus properties of equated i.p. doses of delta 9-THC and CP-47,497 after prolonged training. Despite its potent behavioral effects, CP-47,497, like delta 9-THC, does not resemble standard antipsychotic, antidepressant, antianxiety or hypnotic drugs in simple drug interaction tests. Based on its pharmacology, CP-47,497 exemplifies a simplified structure capable of producing many effects in common with those of delta 9-THC and 9-normethyl-9 beta-OH-hexahydrocannabinol.

Amphetamine↗
PubMed1981

Potent analgetics derived from 9-nor-9 beta-hydroxyhexahydrocannabinol.

Based on the report of morphine-like analgetic activity of 9-nor-9 beta-hydroxyhexahydrocannabinol (HHC), we undertook a study of structural modifications of the C-3 side chain of HHC to optimize the analgetic activity. We ultimately examined four distinct classes of side chains: (1) alkyl (la-lc), (2) arylalkyl (ld-lh), (3) alkoxy (li-lj) and (4) arylalkyloxy (lk-lo). Three of these derivatives (lb, lf, ll) possessed analgetic activity 10X morphine. These studies demonstrate that the C-3 side chain of HHC can be modified in a structure-dependent fashion to yield potent, nonopioid analgetics. In addition, the effect of the 1 methyl-4-phenylbutyloxy side chain is unique among the side chains examined.

Analgesics, Opioid↗
PubMedDate not supplied

Selective and potent analgetics derived from cannabinoids.

Based on the hypothesis that analgetic activity is a dissociable feature of the cannabinoid molecule, we examined modifications of the side chain, the phenolic moiety, and, most significantly, structures that lack the benzopyran functionality present in THC and (--)-9-nor-9 beta-hydroxyhexahydrocannabinol (HHC). A new grouping, the 1-methyl-4-phenylbutyloxy C-3 side chain, elaborates a unique lipopholic region. Replacement of the phenol substituent produced several derivatives which retain analgetic activity in the codeine potency range. Introduction of a weakly basic nitrogen at C-5 and deletion of the axial methyl group in the B ring, two structural changes forbidden by traditional cannabinoid SAR, resulted in a unique family of benzoquinolines with potent analgetic activity. The prototype of this series, levonantradol, exhibits potent and stereospecific analgetic and antiemetic activity.

Analgesics↗