Design, Synthesis, and Opioid Receptor Binding of Some Novel Benzazepine Constrained Leucine Enkephalin Mimetics

An N-substituted 2-benzazepine, previously reported to possess morphine-like analgesic activity in vivo, was adapted for use as a constrained mimic of the N-terminal residues of leucine enkephalin. Molecular modeling was used to evaluate the suitability of the 2-benzazepine nucleus for this purpose. The principle peptide constraint structure, 2-(7-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-2-yl)-ethanoic acid (8) and some structurally related benzazepine analogues were synthesized and incorporated into peptides using solid-phase protocols. Radioligand receptor binding studies were used to evaluate the general opioid receptor affinity of the target compounds. The target constrained peptide (21) demonstrated an affinity for [3H]naloxone-labeled sites (IC50 16 μM) comparable to the corresponding leucine enkephaline analogue.