Binding of ATP-Sensitive Potassium Channel (KATP) Openers to Cardiac Membranes:  Correlation of Binding Affinities with Cardioprotective and Smooth Muscle Relaxing Potencies

Journal of Medicinal Chemistry
1998.0

Abstract

KATP openers (e.g., cromakalim (1), pinacidil (2)) are an important class of compounds with potential clinical indications for diseases such as hypertension, asthma, hair growth, ischemia, and urinary incontinence.1 The major drawback of the first generation agents (e.g., 1, 2) is their lack of tissue selectivity which limits clinical utility.2 The search for tissue selective agents has been hampered by the lack of high-volume screening methods, notably those associated with radioligand binding. Although binding sites for the pinacidil related KATP opener [3H]P-1075 (3) have been reported in intact tissues3 and cells,4 efforts to identify binding sites in membrane preparation which are usually amenable to high volume screening have not been successful. We have recently reported that 3 binds to skeletal muscle membranes with high affinity.5 In this communication we report for the first time the identification of binding sites for 3 in canine myocardial membranes and the correlation of binding affinities to cardioprotective and vasorelaxation potencies for a series of KATP openers.

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