In vitro phamacology of MK-996, a new potent and selective angiotensin II (AT1) receptor antagonist

Autor: Tsing-B. Chen, Kristie A. Faust, Elizabeth M. Naylor, Bradley V. Clineschmidt, Prasun K. Chakravarty, Victor J. Lotti, Robert J. Bendesky, Stacey A. O'Malley, Paul J. Kling, Raymond S.L. Chang, Arthur A. Patchett, William J. Greenlee
Rok vydání: 1994
Předmět:
Zdroj: Drug Development Research. 32:161-171
ISSN: 1098-2299
0272-4391
Popis: MK-996 (N-((4′-((5,7-Dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl) (1,1′-biphenyl)-2-yl) sulfonylbenzamide) interacted in a competitive manner with rabbit aortic angiotensin II (All) receptors as determined by Scatchard analysis of specific binding of [125l]-Sar1lle8-All. MK-996 also exhibited high affinity at All receptors in several tissues from different animal species (Ki = 0.1–0.4 nM). In vitro functional assays utilizing All-induced aldosterone release in rat adrenal cortical cells demonstrated further that MK-996 acts as a competitive, high affinity antagonist of All (pA2 = 10.3) and lacks agonist activity. MK-996 also potently inhibited All-induced contractile response in isolated rabbit aorta and pulmonary artery with a reduction in maximal response. The specificity of MK-996 for All receptors was demonstrated by its lack of activity (IC50> 1 μM) in several other receptor binding assays and its inability to affect in vitro functional responses produced by other agonists. MK-996 demonstrated a very high selectivity for the AT1 compared to AT2 receptor subtype (AT2 IC50 ≥ 2 μM). Direct binding studies using [3H]-MK-996 in rat adrenal indicated specific binding of [3H]-MK-996 is saturable and of high affinity (Kd = 0.47 nM). The specific [3H]-MK-996 binding in rat adrenal represents binding to pharmacologically relevant AT1 receptors as demonstrated by the similar Ki values for various All agonists and antagonists in inhibiting specific 3H-MK-996 and [125l]-All binding to AT1 receptors. Dissociation rate studies of specific [3H]-MK-996 binding indicated a t1/2 of 103 min. This slow dissociation may account for the reduction in maximal responses to All in MK-996 treated isolated blood vessels.
Databáze: OpenAIRE
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