Cyclic somatostatin octapeptide analogues with high affinity and selectivity toward mu opioid receptors

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A series of cyclic conformationally restricted penicillamine containing somatostatin octapeptide analogues have been prepared by standard solid phase synthetic techniques and tested for their ability to inhibit specific [ 125I]CGP 23,996 (des-Ala 1-,Gly 2-[desamino-Cys 3Tyr 11]-dicarba 3,14- somatostatin), [ 3H]naloxone or [ 3H]DPDPE ([D-Pen 2-D-Pen 5]enkephalin) binding in rat brain membrane preparations. We now report structure-activity relationship studies with the syntheis of our most potent and selective mu opioid receptor compound DPheCysTyrDTrpOrnThrPenThrNH 2, which we refer to as Cys 2Tyr 3Orn 5Pen 7-amide. While this octapeptide exhibited high affinity (IC 50 = 2.80 nM) for an apparently single population of binding sites (n H = 0.89 ± 0.1) and exceptional selectivity for mu opioid receptos with an IC 51(DPDPE)/IC 50 (naloxone) ratio of 4,829, it also displayed very low affinity for somatostatin receptors (IC 50 = 22,700 nM). Thus, Cys 2Tyr 3Orn 5 Pen 7-amide may be the ligand of choice for further characterization of mu opioid receptors and for examining the physiological role of this class of receptors.