OXYTOCIN RECEPTOR-BINDING AND UTEROTONIC ACTIVITY OF CARBETOCIN AND ITS METABOLITES FOLLOWING ENZYMATIC DEGRADATION

Metabolites of the analogue 1-deamino-1-carba-2-tyrosine(O-methyl)-oxy tocin (carbetocin) following incubation with a rat kidney homogenate w ere isolated and their pharmacodynamic properties investigated. Apart from the parent compound two metabolites were identified namely desGly NH(2)-cacartetocin (carbetocin metabolite I) and desLeuGlyNH(2)-carbet ocin (carbetocin metabolite II), Both carbetocin, carbetocin metabolit e I and carbetocin metabolite II displayed binding affinities to the m yometrial oxytocin receptor of a similar magnitude as oxytocin. Carbet ocin was found to have agonistic properties on isolated myometrial str ips and it was found to exert this effect through generation of inosit ol phosphates, as is the case for oxytocin. However, maximal contracti le effect of carbetocin was approximately 50% lower than that of oxyto cin (2.70 +/- 0.12 g compared to 5.22 +/- 0.26 g) and EC50 was approxi mately ten times higher (48.0 +/- 8.20 nM compared to 5.62 +/- 1.22 nM ). Neither carbetocin metabolite I nor carbetocin metabolite II were a ble to contract isolated myometrial tissue. All three compounds displa yed antagonistic properties against oxytocin in vitro, with carbetocin being the strongest inhibitor (pA(2) = 8.21) and carbetocin metabolit e II (pA(2) = 8.01) being stronger than carbetocin metabolite I (pA(2) = 7.81). These results indicate that carbetocin is a partial agonist/ antagonist to the oxytocin receptor while the two metabolites carbetoc in metabolite I and carbetocin metabolite II are pure antagonists. All three analogues bound to the myometrial vasopressin V-1 receptor, alb eit with much lower affinities than to the oxytocin receptor. Carbetoc in metabolite II showed the weakest binding affinity of 33.7 +/- 7.34 nM compared to 7.24 +/- 0.29 nM for carbetocin and 9.89 +/- 2.80 nM fo r carbetocin metabolite I. Only carbetocin bound to the renal vasopres sin V-2 receptor though the binding affinity was very low (61.3 +/- 14 .6 nM). (C) 1998 Elsevier Science B.V. All rights reserved.