Conformational Aspects of Differences in Requirements for Oxytocin and Vasopressin Receptors

Abstract

Conformational energy calculations were carried out on three non-peptide antagonists of oxytocin and vasopressin: penicilide (compound 1; selective for oxytocin receptors), 1- {1-[4-(3-acetylaminopropoxy (benzoyl]-4-piperidyl}-3,4-dihydro-2(1H)-quinoline (compound 2; selective for vasopressin V₁ receptors) and 5-dimethylamino-1-{(2-methylbenzylamino)-benzoyl}-2,3,4,5–tetrahydro-1H-benzapine (compound 3; selective for vasopressin V₂ receptors). The obtained low-energy conformations of compound 1 were compared with low-energy conformations of oxytocin (OT) and low-energy conformations of compounds 2 and 3 were compared with low-energy conformations of arginine vasopressin (AVP). It was found that the affinity of the non-peptide antagonists and their selectivity for vasopressin and oxytocin receptors is probably connected with mimicking the aromatic rings of the Tyr² and the Phe³ residues of AVP in the case of compounds 2 and 3 and with mimicking the Tyr² residue and the Ile³ or Leu⁸ residues of OT by the outer benzene ring and the isobutyl group of compound 1. Application of the results in the design of more potent non-peptide antagonists of OT and VP is also discussed.