Synthesis and pharmacology of cannabimimetic indoles

Since the characterization of the active constituent of marijuana, Δ 9-tetrahydrocannabinol (Δ9-THC), by Gaoni et al. in 1964, many cannabinoids and their metabolites have been described. Considerable effort has gone into modifying the structure of cannabinoids, as well as in developing compounds structurally diverse from the classical dibenzopyran structure. Hence, there are now two main classes of cannabinoids: classical cannabinoids; and non-classical cannabinoids that include endogenous cannabinoids, such as anandamide and the cannabimimetic indoles.; This research will focus on synthesis of cannabinoid analogues as probes for the cannabinoid receptor, where the syntheses of cannabimimetic indoles are described. The cannabimimetic indoles were investigated to expand the data available for the structure-activity relationships (SAR) for cannabinoids at the CB₁ and CB₂ receptors.; The cannabimimetic indoles investigated were the 3-(4-propyl-1-naphthoyl)indoles, 3-(4-ethyl-1-naphthoyl)indoles and 3-(4-butyl-1-naphthoyl)indoles, and a new rigid indole analogue. Pharmacology data has shown that some naphthoylindoles with nitrogen substituents of three to five carbon atoms have affinity for the cannabinoid brain receptor (CB1) superior to that of Δ9-THC.; The 3-(4-alkyl-1-naphthoyl)indoles were prepared by first making the corresponding 1-alkylnaphthalene which was converted into the corresponding 4-alkyl-1-naphthoic acid by reaction with N,N-diphenylcarbamoyl chloride to prepare an N,N-diphenylamide. Subsequent saponification gave the carboxylic acid. This acid was converted to the acyl chloride by reaction with oxalyl choride. Friedel-Crafts acylation of indoles with the acyl chloride, using ethylaluminum dichloride as the Lewis acid gave the 3-(4-alkyl-1-naphthoyl)indole. Pharmacology data revealed that some of these indole derivatives have very high affinity for the cannabinoid receptor, while others have only modest affinity.; The rigid indole analogue was prepared from methyl-2-hydroxy-1-naphthoate via a Sonogashira reaction, cross-coupling the appropriate terminal alkynes with an N,O-bis-triflate derived from oxindole. The product of this coupling was selectively deprotected at the indole nitrogen. After hydrogenation to the alkane, N-alkylation of the indole gave the N-alkyl indole. Saponification, conversion to the acyl chloride, and finally an intramolecular cyclization using the mild Lewis acid EtAlCl₂ gave the desired target rigid indole.; Pharmacological evaluation of the rigid analogue reveals that this compound has much lower affinity for the CB₁ receptor than the natural cannabinoids Δ 9-THC and Δ8-THC. This cannabinoid is considered as having negligible CB₁ receptor affinity.