Novel peptidic mu opioid antagonists: pharmacologic characterization in vitro and in vivo

A series of six synthetic octapeptides, structurally related to somatostatin, demonstrate high affinity and selectivity for mu opioid receptors in radioligand binding assays. The compounds, D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), D-tetrahydroisoquinoline carboxylic acid (D-Tic)-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (D-Tic-CTP), D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (D-Tic-CTOP) and D-Tic-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (D-Tic-CTAP), were tested in vitro and in vivo for agonist and antagonist potency and selectivity. In vitro bioassays included the guinea pig ileum, mouse vas deferens and rabbit vas deferens. In vivo tests included hotplate antinociception and gastrointestinal transit inhibition, performed in mice. In vitro, all six derivatives were competitive, highly selective mu antagonists (pA2 values from 6.4-7.9). The compounds demonstrated varying degrees of intrinsic agonist activity especially in the mouse vas deferens, the least active being CTAP and D-Tic-CTAP, which showed no mu or kappa agonist actions, and delta activity only at very high (greater than 3 microM) concentrations. In vivo, none of these compounds showed antinociceptive actions when administered i.c.v. in mice. All were competitive mu antagonists in the hotplate antinociception test.(ABSTRACT TRUNCATED AT 250 WORDS)