Bis-penicillamine enkephalins possess highly improved specificity toward delta opioid receptors.

Abstract

The conformationally restricted, cyclic, disulfide-containing, enkephalin analogs [2-D-penicillamine-5-L-penicillamine]-enkephalin .**GRAPHIC**. and [2-D-penicillamine-5-D-penicillamine]-enkephalin .**GRAPHIC**. were synthesized by solid-phase methods. Selectivities of these analogs for a single class of opioid receptor were investigated by examining relative potencies in the mouse vas deferens assay, in which the functional receptor is the .delta. receptor, vs. the guinea pig ileum assay, in which the .mu. receptor is the functional receptor and by determining their relative abilities to displace the prototypical .delta. receptor ligand [D-Ala2-D-Leu5]-enkephalin and the prototypical .mu. receptor ligand naloxone from rat brain membrane preparations. .**GRAPHIC**. and .**GRAPHIC**. exhibited .delta. receptor selectivities of 1088 and 3164, respectively, in the bioassays, and 371 and 175, respectively, in the binding assays. Compared with the previously reported .delta. receptor selective analogs, [D-Ala2-D-Leu5]-enkephalin, [D-Ser2-Leu5-Thr6]-enkephalin and [D-Thr2-Leu5-Thr6]-enkephalin, the bis-Pen-containing analogs provide an order of magnitude increase in .delta. receptor selectivity.