• Article

Evaluation of agonist-antagonist properties of nitrogen mustard and cyano derivatives of Delta(8)-tetrahydrocannabinol

Delta(8)-Tetrahydrocannabinol (Delta(8)-THC) is a naturally occurring cannabinoid with a characteristic pharmacological profile of in vivo effects. Previous studies have shown that modification of the structure of Delta(8)-THC by inclusion of a nitrogen-containing functional group alters this profile and may alkylate the cannabinoid receptor, similar to the manner in which beta-funaltrexamine (beta-FNA) alkylates the mu-opioid receptor. Two novel analogs of Delta(8)-THC were synthesized: a nitrogen mustard analog with a dimethylheptyl side chain (NM-Delta(8)-THC) and a cyano analog with a dimethylpentyl side chain (CY-Delta(8)-THC). Both analogs showed high affinity for brain cannabinoid receptors and when administered acutely, produced characteristic Delta(9)-THC-like effects in mice, including locomotor suppression, hypothermia, antinociception and catalepsy. CY-Delta(8)-THC shared discriminative stimulus effects with CP 55,940; for NM-Delta(8)-THC, these effects also occurred, but were delayed. Although both compounds attenuated the effects of Delta(9)-THC in the mouse behavioral tests, evaluation of potential antagonist effects of these compounds was complicated by the fact that two injections of Delta 9-THC produced similar results, suggesting that acute tolerance or desensitization might account for the observations. NM-Delta(8)-THC, but not CY-Delta(8)-THC, attenuated the discriminative stimulus effects of CP 55,940 in rats several days following injection. Hence, addition of a nitrogen-containing functional group to a traditional cannabinoid structure does not eliminate agonist effects and may produce delayed attenuation of cannabinoid-induced pharmacological effects. (C) 1997 Elsevier Science Ltd

Citation

Wiley, J., Compton, D. R., Gordon, P. M., Siegel, C., Singer, M., Dutta, A., ... Martin, B. R. (1996). Evaluation of agonist-antagonist properties of nitrogen mustard and cyano derivatives of Delta(8)-tetrahydrocannabinol. Neuropharmacology, 35(12), 1793-1804.