The stereochemical requirements of the novel δ-opioid selective dipeptide antagonist TMT-TIC

Five conformationally constrained dipeptide TMT-L-Tic analogues have been synthesized and evaluated for their bioactivity using in vitro bioassays. The most potent and selective analogue (2S,SR)-TMT-L-Tic showed 9 nM binding affinity and 4000-fold selectivity for the delta vs mu opioid receptor. The lowest-energy conformation of(2S,3R)-TMT-L-Tic is suggested to be bioactive one in which the chi(1) torsional angle is trans for TMT and gauche (+) for Tic. (C) 1997 Elsevier Science Ltd.