Oldziej S, Ciarkowski J, Liwo A, Shenderovich M D, Grzonka Z
Department of Chemistry, University of Gdansk, Poland.
J Recept Signal Transduct Res. 1995 Jan-Mar;15(1-4):703-13. doi: 10.3109/10799899509045250.
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.
青霉素（化合物1；对催产素受体具有选择性）、1-（1-[4-（3-乙酰氨基丙氧基）苯甲酰基]-4-哌啶基）-3,4-二氢-2（1H）-喹啉（化合物2；对血管加压素V1受体具有选择性）和5-二甲基氨基-1-（2-甲基苄基氨基）-苯甲酰基-2,3,4,5-四氢-1H-苯并氮杂卓（化合物3；对血管加压素V2受体具有选择性）。将化合物1获得的低能构象与催产素（OT）的低能构象进行比较，将化合物2和3的低能构象与精氨酸血管加压素（AVP）的低能构象进行比较。结果发现，非肽拮抗剂的亲和力及其对血管加压素和催产素受体的选择性可能与以下情况有关：在化合物2和3的情况下，模拟AVP的Tyr2和Phe3残基的芳香环；在化合物1的情况下，通过外苯环和异丁基模拟OT的Tyr2残基以及Ile3或Leu8残基。还讨论了这些结果在设计更有效的OT和VP非肽拮抗剂中的应用。
