Selective ligands for opioid receptors. beta-Cyclopropylalanyl containing analogs of enkephalin.

Abstract

The synthesis and resolution of the amino acid β‐cyclopropylalanine (Cpr) and its incorporation into four enkephalin analogs is reported. The analogs prepared were: Tyr ‐ l ‐ Cpr ‐ Gly ‐ Phe ‐ Pen (des ‐ COOH ‐ Nle = n ‐ pentylamide = Pen) (l‐Cpr2‐Pen5‐ENK), Tyr‐d‐Cpr‐Gly‐Phe‐Pen (d‐Cpr2‐Pen5‐ENK), l‐Cpr‐Tyr‐d‐Ala‐Gly‐Phe‐Pen (l‐Cpr0‐d‐Ala2‐Pen5‐ENK) and d‐Cpr‐Tyr‐d‐Ala‐Gly‐Phe‐Pen (d‐Cpr0‐d‐Ala2‐Pen5‐ENK). Each was tested for its ability to inhibit the field stimulated guinea pig ileum (GPI) and rat vas deferens (RVD) and the results compared to the effect d‐Ala2‐d‐Leu5‐enkephalin (DADLE) has on the same preparations. The results show that at concentrations up to 10‐5 m all four analogs, as well as DADLE, are full agonists on the GPI preparation. The concentrations necessary to produce a 50% inhibition of the twitch response were, DADLE, 3.5 °× 10‐8 m; l ‐ Cpr0‐d‐Ala2‐Pen5‐ENK, 6.0 × 10‐8 m; d‐Cpr2‐Pen5‐ENK, 1.1 × 10‐7 m; l‐Cpr2‐Pen5‐ENK, 1.2 × 10‐6 m and d‐Cpr0‐d‐Ala2‐Pen5‐ENK, > 10‐5 m. On RVD a different result was observed with only DADLE (1.3 × 10‐6 m) and l‐Cpr0‐Pen5‐enkephalin (1.8 × 10‐6 m) showing full agonist activity. d‐Cpr2‐Pen5‐ENK was a partial agonist (29 · 5% inhibition of the twitch at 10‐5 m) while d‐Cpr0‐d‐Ala2‐Pen5‐ENK and l‐Cpr2‐Pen5‐ENK did not inhibit the twitch at concentrations up to 10‐5 m. These compounds which were inactive or of low potency on each preparation were also tested as antagonists. Only d‐Cpr2‐Pen5‐ENK was an antagonist (pA2 = 6.09) versus DADLE on RVD while d‐Cpr0‐d‐Ala2‐Pen5‐ENK was inactive as an antagonist on both GPI and RVD. d‐Cpr2‐Pen5‐ENK, therefore, represents the first enkephalin analog to be categorized as a mixed agonist‐antagonist.