Cannabimimetic indoles, pyrroles and indenes.
In the course of efforts to develop new nonsteroidal antiinflammatory agents, it was discovered that 1-aminoalkyl-3-aroylindoles have affinity for the cannabinoid brain (CB1) receptor. This led to the synthesis of well over 100 cannabimimetic aminoalkylindoles by the group at Sterling Winthrop, and to the development of structure-activity relationships (SAR) for these compounds. These SAR require a heterocyclic aminoethyl group attached to the indole nitrogen, and a 1-naphthoyl group at C-3 for significant receptor affinity. Other workers subsequently demonstrated that an aminoalkyl group was not necessary for cannabinoid activity, but that an N-alkyl group of four to 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. Comprehensive SAR for this group of cannabinoids have been developed. Two groups have described cannabimimetic indenes, which have been employed as rigid models for the receptor interactions of cannabimimetic indoles with the CB1 receptor. There is some evidence that the indoles interact at a somewhat different site on the receptor than traditional cannabinoids.
Huffman
J W
JW
Howard L. Hunter Chemistry Laboratory, Clemson University, Box 341905, Clemson, South Carolina, 29634-1905, USA.
D000818:Animals; D002186:Cannabinoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D002186:Cannabinoids; D007192:Indenes; D007211:Indoles; D011758:Pyrroles