Conformational aspects of differences in requirements for oxytocin and vasopressin receptors.
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-tetrahyd ro-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.
Department of Chemistry, University of Gdansk, Poland.
S
S
Oldziej
J
J
Ciarkowski
A
A
Liwo
M D
MD
Shenderovich
Z
Z
Grzonka
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D007783:Lactones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D010121:Oxytocin / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015363:Quinolones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017483:Receptors, Vasopressin / Q000378:metabolism*; D013816:Thermodynamics; D014667:Vasopressins / Q000737:chemistry
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D007783:Lactones; D010880:Piperidines; D015363:Quinolones; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; C104408:penicilide; D014667:Vasopressins; C068644:OPC 21268; C076251:mozavaptan; D010121:Oxytocin