text: Nonclassic antagonists lack the urea, thiourea, or amide groups typical of the classic TRPV1 ligands. Two major structural types of nonclassic antagonists have been discovered. First there are the imidazole derivatives. Starting from a 4,6-disubstituted benzimidazole lead structure, a series of 4,5-biarylimidazoles capable to block both capsaicin and acid-induced calcium influx in TRPV1-expressing Chinese hamster ovary cells. Imidazole (fig. 8a) was identified as a highly potent and orally bioavailable TRPV1. Another class are the diaryl ethers and amines. Compounds from a quinazoline series can be considered as conformationally restricted analogs of a biarylamide series. In terms of activity 5-isoquinoline was found the most active among and ranked in the order of 5-isoquinoline > 8-quinoline > 8-quinazoline > 8-isoquinoline ≥ cinnoline > phthalazine > quinoxaline > 5-quinoline e.g.  AMG-517 (fig. 8b), although it lacks any recognizable carbonyl motif it still potently blocks capsaicin, proton, and heat activation of TRPV1 in vitro and shows a good tolerability profile. Also, the clinical candidates from Janssen, Abbott and Merck pharmaceuticals (fig. 8c) having a 5-aminoisoquinoline group as a common feature suggesting that there is a key interaction of this group at the receptor site for TRPV1 antagonist activity.