Cannabinoid agonist activity

Sanofi-Synthelabo researchers discovered pyrazole 53 and analogs to have potent Cannabinoid receptor-1 (CB-1) antagonist/inverse agonist activity and have progressed 53 into development for treatment of obesity and alcohol dependence. The synthesis of 53 was accomplished by heating the diketone sodium salt 51 with the aryl hydrazine hydrochloride in acetic acid to provide the intermediate 52, which was further derivatized... 

Novartis AG has filed a patent application on novel naphthalene derivatives as potent cannabinoid agonists, especially at the CBi receptor [208]. One compound was specifically claimed, the naphthalene derivative (319), which exhibited CBi binding with a if value of 15 nM. This compound was also active in an in vivo model of neuropathic pain, reversing hyperalgesia... 

In addition, Novartis filed a patent application on a series of quinazolines as cannabinoid agonists [209]. Compound (320) is one of the two compounds specifically claimed and exhibited CBi and CB2 binding with if values of 34 and 11 nM, respectively. It was shown to be a full agonist at the CBi receptor with an EC50 of 132nM (no functional data for the CB2 receptor). Compound (320) was also active in the neuropathic pain model described above with an ED50 of 0.5mg/kg after oral dosing. 

A second antagonist, AM 630 (24b), a novel aminoalkylindole, was found to attenuate the ability of some cannabinoids to inhibit electrically-evoked twitches of the mouse isolated vas deferens [114]. AM 630 was a more potent antagonist of d9-THC than of anandamide (Kd of 14.0 and 278.8 nM, respectively). It was suggested that the receptors for which AM 630 has the highest activity may not be CB, cannabinoid receptors. This is supported by the observation that AM 630 is actually a cannabinoid agonist in the myenteric plexus - muscle preparation [115]. Yamada et al. [116] showed that isothiocyanate derivatives of pravadoline can serve as potential electrophilic affinity ligands for CB],... 

The mechanism of cannabinoid antiemetic activity is not well understood. As pointed out above, it does not seem to involve CB, or CB2. Fan has shown that anandamide and some synthetic cannabinoid agonists inhibit the activation of 5-HT3 receptors in rat nodose ganglion neurons [61]. These receptors are known to mediate emetic activity. However, we have found that HU-211 does not bind to 5-HT3 receptors (unpublished observations). Hence, although cannabinoids may act, in part at least, through this serotonin receptor, this mode of action does not account for the total activity. 

Hwang JH, Yaksh TL (1997) The effect of spinal GABA receptor agonists on tactile aUodynia in a surgically-induced neuropathic pain model in the rat. Pain 70 15-22 Ibrahim MM, Porreca F, Lai J, Albrecht PJ, Rice FL, Khodorova A, Davar G, Makriyannis A, Vanderah TW, Mata HP, Malan TP Jr (2005) CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sd U S A 102 3093-3098... 

Sugiura, T., Kondo, S., Kishimoto, S., Miyashita, T., Nakan, S., Kodaka, T., et al. (2000). Evidence that 2-arachidonoylglycerol but no N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells. Journal of Biological Chemistry, 275, 605-612. 

Breivogel CS, Childers SR (2000) Cannabinoid agonist signal transduction in rat brain comparison of cannabinoid agonists in receptor binding, G-protein activation, and adenylyl cyclase inhibition. J Pharmacol Exp Ther 295 328-336... 

Compton DR, Aceto MD, Lowe J, Martin BR (1996) In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A) inhibition of/19-tetrahydrocannabmol-induced responses and apparent agonist activity. J Pharmacol Exp Ther 277 586-594... 

Fan P (1995) Cannabinoid agonists inhibit the activation of 5-HT3 receptors in rat nodose ganglion neurons. J Neurophysiol 73 907-910... 

Pan X, Ikeda SR, Lewis DL (1998) SR 141716A acts as an inverse agonist to increase neuronal voltage-dependent Ca2-t currents by reversal of tonic CB 1 cannabinoid receptor activity. Mol Pharmacol 54 1064-1072... 

Petitet F, Jeantaud B, Reibaud M, Imperato A, DubroeucqMC (1998) Complex pharmacology of natural cannabinoids evidence for partial agonist activity of A9-tetrahydrocanna-binol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life Sci 63 PL1-PL6... 

Pinto JC, Potie F, Rice KC, Boring D, Johnson MR, Evans DM, Wilken GH, Cantrell CH, Howlett AC (1994) Cannabinoid receptor binding and agonist activity of amides and esters of arachidonic acid. Mol Pharmacol 46 516-522... 

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