Cannabimimetic indoles, pyrroles and indenes

In the course of efforts to develop new nonsteroidal antiinflammatory agent s, it was discovered that 1-aminoalkyl-3-aroylindoles have affinity for the cannabinoid brain (CB1) receptor. This led to the synthesis of well over 1 00 cannabimimetic aminoalkylindoles by the group at Sterling Winthrop, and to the development of structure-activity relationships (SAR) for these comp ounds. These SAR require a heterocyclic aminoethyl group attached to the in dole nitrogen, and a 1-naphthoyl group at C-3 for significant receptor affi nity. Other workers subsequently demonstrated that an aminoalkyl group was not necessary for cannabinoid activity, but that an N-alkyl group of four t o six carbons was sufficient. This led to the discovery that 1-propyl-3-(1- naphthoyl)indole is a selective ligand for the peripheral cannabinoid (CB2) receptor, and to the development of a series of cannabimimetic pyrroles. C omprehensive SAR for this group of cannabinoids have been developed. Two gr oups have described cannabimimetic indenes, which have been employed as rig id models for the receptor interactions of cannabimimetic indoles with the CB1 receptor. There is some evidence that the indoles interact at a somewha t different site on the receptor than traditional cannabinoids.