Showing papers by "Billy R. Martin published in 1998"

Structure-activity relationships of indole- and pyrrole-derived cannabinoids.

Abstract: Early molecular modeling studies with Δ 9 -tetrahydrocannabinol (Δ 9 -THC) reported that three discrete regions which interact with brain cannabinoid (CB1) receptors corresponded to the C-9 position of the cyclohexene ring, the phenolic hydroxyl and the carbon side chain at the C3 position. Although the location of these attachment points for aminoalkylindoles is less clear, the naphthalene ring, the carbonyl group and the morpholinoethyl group have been suggested as probable sites. In this study, a series of indole- and pyrrole-derived cannabinoids was developed, in which the morpholinoethyl group was replaced with another cyclic structure or with a carbon chain that more directly corresponded to the side chain of Δ 9 -THC and were tested for CB1 binding affinity and in a battery of in vivo tests, including hypomobility, antinociception, hypothermia and catalepsy in mice and discriminative stimulus effects in rats. Receptor affinity and potency of these novel cannabinoids were related to the length of the carbon chain. Short side chains resulted in inactive compounds, whereas chains with 4 to 6 carbons produced optimal in vitro and in vivo activity. Pyrrole-derived cannabinoids were consistently less potent than were the corresponding indole derivatives and showed pronounced separation of activity, in that potencies for hypomobility and antinociception were severalfold higher than potencies for hypothermia and ring immobility. These results suggest that, whereas the site of the morpholinoethyl group in these cannabinoids seems crucial for attachment to CB1 receptors, the exact structural constraints on this part of the molecule are not as strict as previously thought.

CB1 Receptor Antagonist Precipitates Withdrawal in Mice Exposed to Δ9-Tetrahydrocannabinol

Abstract: Although tolerance to cannabinoids has been well established, the question of cannabinoid dependence had been very controversial until the discovery of a cannabinoid antagonist, SR141716A. The objective of this study was to develop and characterize a mouse model of precipitated withdrawal indicative of cannabinoid dependence. Using a dosing regimen known to produce pharmacological and behavioral tolerance, mice were treated with Δ9-tetrahydrocannabinol (Δ9-THC) twice a day for 1 wk. SR141716A administration after the last Δ9-THC injection promptly precipitated a profound withdrawal syndrome. Typical withdrawal behavior was an increase in paw tremors and head shakes that was accompanied with a decrease in normal behavior such as grooming and scratching. Of the three Δ9-THC regimens tested, daily Δ9-THC injections of 10 and 30 mg/kg produced the greatest number of paw tremors and head shakes and the least number of grooms after challenge with SR141716A. Precipitated withdrawal was apparent after 2, 3, 7 and 14 days of treatment based on an increase in paw tremors in Δ9-THC-treated mice as compared with vehicle-treated mice. These findings are consistent with SR141716A-precipitated withdrawal in rats. Moreover, these results suggest that mice are a viable model for investigating dependence to cannabinoids.

Evaluation of Cannabinoid Receptor Agonists and Antagonists Using the Guanosine-5′-O-(3-[35S]thio)-triphosphate Binding Assay in Rat Cerebellar Membranes

Abstract: Cannabinoid receptors are members of the superfamily of G protein-coupled receptors. Their activation has previously been shown to stimulate guanosine 5'-O-(3-[35S]thio)-triphosphate ([35S]GTP gamma S) binding in a range of brain regions using both membrane preparations and autoradiography. This study evaluates the activities of structurally diverse cannabinoid receptor ligands in the GTP gamma S binding assay, comparing the relationship between receptor binding and activation and also examining efficacy differences between compounds. Using rat cerebellar membrane preparations, the effects of GDP concentration on GTP gamma S binding and the activities of a range of cannabinoid receptor ligands, including the CB1 selective antagonist SR141716A, were investigated. GDP concentration was found to have differing effects on cannabinoid-stimulated [35S]GTP gamma S binding depending on the nature of the agonist used. The stimulation produced by high efficacy compounds, such as CP 55,940 and WIN 55212-2, was increased by raising the GDP concentration, but that of a low efficacy agonist, (-)-delta-tetrahydrocannabinol, was decreased. Of the cannabinoid compounds tested, a wide range of potencies (EC50) and levels of maximal stimulation (Emax) were observed. These ranged from CP 55,244 (Emax of 165, 148-183%, and an EC50 of 0.47, 0.22-0.96, nM) through (-)-delta-tetrahydrocannabinol, cannabinol and anandamide, which produced no concentration-dependent stimulation of [35S]GTP gamma S binding under the same conditions. SR141716A competitively antagonized all the agonists against which it was tested, providing equilibrium dissociation constants (Kd values) in the sub-nanomolar range (0.06-0.40 nM), implicating a CB1 receptor mediated response. These results provide a more detailed characterization of the cannabinoid-stimulated [35S]GTP gamma S binding assay than has previously been reported.

Anandamide, an Endogenous Cannabinoid, Has a Very Low Physical Dependence Potential

Abstract: Using N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide · HCl (SR 141716A), a cannabinoid antagonist, several investigators (deFonseca et al. , 1997; Aceto et al. , 1995,1996; Tsou et al. , 1995) demonstrated physical dependence on THC [Δ 9 -tetrahydrocannabinol]. This demonstration prompted us to determine whether anandamide, an endogenous cannabinoid agonist, would also produce physical dependence. A low-dose regimen (10, 20, 40 and 40) or a high-dose regimen (25, 50, 100 and 100) expressed as mg/kg/24 hr was infused i.p. on a continuous basis, from days 1 through 4, respectively. During the infusion, especially at the high-dose regimen, the rats became immobile and developed eyelid ptosis. Abrupt discontinuation of anandamide did not elicit rebound behavioral activity. Neither arachidonic acid, a precursor and metabolite of anandamide (50, 100, 200 and 200 mg/kg/24 hr on days 1 through 4, respectively), nor 2-Me-F-AN [2-methylarachidonyl-(2′-fluoroethyl)-amide], a metabolically stable analog of anandamide (5, 10, 20 and 20 mg/kg/24 hr for 4 days, respectively), had remarkable effects. Notably, groups pretreated with anandamide or 2-Me-F-AN and challenged with SR 141716A did not show significantly elevated behavioral scores when compared with SR 141716A controls. On the other hand, nearly all groups receiving SR 141716A showed significant activation of these behaviors compared with vehicle controls, which suggests that this cannabinoid antagonist itself was activating behavior. We concluded that anandamide has little if any capacity for physical dependence. The finding that SR 141716A activated behavior supports the hypothesis that the cannabimimetic system exerts a depressant effect in the CNS.

Potent Cyano and Carboxamido Side-Chain Analogues of 1‘,1‘-Dimethyl-Δ8-Tetrahydrocannabinol

Abstract: The synthesis and pharmacological profile of several cyano (1a−e) and carboxamido (2a−h) side-chain-substituted analogues of 1‘,1‘-dimethyl-Δ8-THC are described. Commercially available cyano compound 3 was transformed to the resorcinol 6 in a three-step sequence. Condensation of 6 with p-menth-2-ene-1,8-diol formed the THC 7a which, with sodium cyanide/DMSO, gave 1b. Protection of the phenol in 7a as the MOM derivative provided the common intermediate 8 for the synthesis of 1a,c,e. Compound 1d was also synthesized from 7a via the aldehyde 9a. Base hydrolysis of 1b gave the acid 10 which, via its acid chloride and subsequent treatment with the appropriate amine, formed the target compounds 2a−h. The pharmacological profile indicated that the cyano analogues 1a−e had very high CB1 binding affinity (0.36−13 nM) and high in vivo potency as agonists. Two analogues (1a,b) had extremely high potency in the mouse tetrad tests. The dimethylcarboxamido analogue 2a showed a similar profile to 1a,b. The high potency ...

Water soluble derivatives of cannabinoids

Abstract: Water-soluble esters of tetrahydrocannabinoids, which are well-suited for administration in therapeutic aqueous formulations, having following general formula: ##STR1## wherein a - - - b designates a 9(10) or a 9(8) double bond, R' is a --(CH 2 ) n -- linkage group where n is 1-8, and R is a -(CZ 2 ) n - linkage group where n is 6 or more and Z independently is H or a substituent such as a lower alkyl group, and the pharmaceutically acceptable salts of these compounds.

Compounds and pharmaceutical compositions thereof for eliciting analgesic effects

Abstract: The present invention relates to treatment of pain with a new class of analgesic compounds. More particularly, the present invention relates to a method for reducing pain of a patient involving administering to a patient an effective amount of an aryl substituted olefinic amine compound. In one aspect, the inventive method of reducing pain in a patient involves use of metanicotine compounds as the analgesic agent.

Enantioselective Synthesis and Pharmacology of 11-Hydroxy-(1′S,2′R)-dimethylheptyl-Δ8-THC.

Abstract: An enantioselective synthesis of the (1' S ,2' R )-dimethylheptyl cannabinoid side chain has been developed and employed in the synthesis of 11-hydroxy-(1' S ,2' R )-dimethylheptyl-Δ 8 -THC ( 3 ). Pharmacology, in vivo and in vitro, indicate ( 3 ) to be one of the most potent traditional cannabinoids known.

Use of (e)-metanicotine derivatives for eliciting analgesic effects

Abstract: The present invention relates to treatment of pain with a new class of analgesic compounds. More particularly, the present invention relates to a method for reducing pain of a patient involving administering to a patient an effective amount of an aryl substituted olefinic amine compound. In one aspect, the inventive method of reducing pain in a patient involves use of metanicotine compounds as the analgesic agent.