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

The conformationally restricted, cyclic, disulfide-containing, enkephalin analogs [2-D-penicillamine, 5-L-penicillamine]enkephalin [(D-Pen2,L-Pen5]enkephalin) and [2-D-penicillamine, 5-D-penicillamine]enkephalin [(D-Pen2,D-Pen5]enkephalin) were synthesized by solid-phase methods. Selectivities of th...

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Published in:	Proceedings of the National Academy of Sciences - PNAS 1983-10, Vol.80 (19), p.5871-5874
Main Authors:	Mosberg, H I, Hurst, R, Hruby, V J, Gee, K, Yamamura, H I, Galligan, J J, Burks, T F
Format:	Article
Language:	eng
Subjects:	Animals Binding, Competitive Biological Assay Brain - metabolism enkephalin Enkephalin, D-Penicillamine (2,5) Enkephalin, Leucine - analogs & derivatives Enkephalin, Leucine - metabolism Enkephalin, Leucine - pharmacology Enkephalin, Leucine-2-Alanine - analogs & derivatives Enkephalins - chemical synthesis Enkephalins - metabolism Enkephalins - pharmacology Isomerism Kinetics Muscle Contraction - drug effects Naloxone - metabolism Oligopeptides - metabolism opiates Rats Receptors, Opioid - metabolism Receptors, Opioid, delta Structure-Activity Relationship
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Summary:	The conformationally restricted, cyclic, disulfide-containing, enkephalin analogs [2-D-penicillamine, 5-L-penicillamine]enkephalin [(D-Pen2,L-Pen5]enkephalin) and [2-D-penicillamine, 5-D-penicillamine]enkephalin [(D-Pen2,D-Pen5]enkephalin) 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, versus 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. Based on these comparisons [D-Pen2,L-Pen5]- and [D-Pen2,D-Pen5]enkephalin exhibited delta receptor selectivities of 1,088 and 3,164, 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.
ISSN:	0027-8424 1091-6490