Synthesis and pharmacological characterization in vitro of cyclic enkephalin analogs: effect of conformational constraints on opiate receptor selectivity

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Abstract
Using a combination of solid-phase and solution methods, a series of cyclic [Leu5]enkephalin analogs were synthesized by substitution of D-.alpha.-.omega.-diamino acids in position 2 of the enkephalin sequence and cyclization of the .omega.-amino group to the C-terminal carboxy group of leucine. Cyclic analogs containing D-.alpha.,.beta.-diaminopropionic acid, D-.alpha.,.gamma.-diaminobutyric [Abu] acid, D-ornithine or D-lysine in position 2 and the [D-Leu5] and [des-Leu5] analogs of D-lysine showed, in general, high potency in the guinea pig ileum (GPI) assay and low potency in the mouse vas deferens (MVD) assay. IC50 [median inhibitory concentration] (MVD)/IC50 (GPI) ratios from 3.1-29.4 were obtained, indicating the preference of the cyclic analogs for .mu. receptors over .omega. receptors. With 2 exceptions, preferential affinity for .mu. receptors is reflected in the Ki [inhibition constant] ratios determined in parallel binding assays using [3H]naloxone and [3H] [D-Ala2,D-Leu5]enkephalin as .mu. and .delta. receptor selective radioligands, respectively. Comparison of the pharmacological profiles of the cyclic analogs with those of their corresponding open-chain analogs, [D-Ala2,Leu5]enkephalinamide, [D-Abu2,Leu5]enkephalinamide, [D-Nva2,Leu5]enkephalinamide and [D-Nle2,Leu5]enkephalinamide, revealed that the pronounced .mu. character is a direct consequence of the conformational constraints introduced by cyclization. This finding is in agreement with the concept of different conformational requirements of .mu.- and .omega.-opiate receptors and raises the possibility of manipulating opiate receptor selectivity by varying the type and degree of conformational restriction.