Zeneca ZD6169 and Its Analogs from a Novel Series of Anilide Tertiary Carbinols: In vitro KATP Channel Opening Activity in Bladder Detrusor

Autor: J.H. Li, G.D. Yasay, P. Zografos, S.T. Kau, C.J. Ohnmacht, K. Russell, J.R. Empfield, F.J. Brown, D.A. Trainor, A.D. Bonev, T.J. Heppner, M.T. Nelson
Rok vydání: 1995
Předmět:
Zdroj: Pharmacology. 51:33-42
ISSN: 1423-0313
0031-7012
DOI: 10.1159/000139314
Popis: The potassium (K+) channel opening activity of Zeneca ZD6169 and one of its pyridylsulfonyl analogs from the anilide tertiary carbinol series was ascertained. Their mechanoin-hibitory effects on the myogenic activity of the guinea pig bladder detrusor muscle were measured in a set of functional assays. Elevating the K+ concentration in the tissue bath from 15 to 80 mmol/l increased the IC50 value of ZD6169 from 1.61 ± 0.22 to 223 ± 37 µmol/l. This result suggests that ZD6169 may act as a K+ channel opener. Similar to the prototypic ATP-sensitive K+ (KATP) channel opener cromakalim, the K+ channel openers from the anilide tertiary carbinol series displayed stereoselective mechanoinhibitory activity only in the test protocol in which the detrusor was stimulated with 15 mmol/l KC1. Being the active enantiomer, ZD6169 has an activity more than 30-fold higher than the less active enantiomer. ZD6169 at 10 µmol/l hyperpolarized the guinea pig detrusor membrane potential by 6.1 ± 1.2 mV and increased the whole cell KAtp current in isolated guinea pig smooth muscle cells by 34.9 ± 7.9 pA. This is comparable to the increase of 26.8 ± 5.0 pA obtained with 10 µmol/l of lemakalim, the active enantiomer of cromakalim. The K+ channel opening activity of ZD6169 and the pyridylsulfonyl analog was competitively antagonized by the KAtp channel blocker glibenclamide in the guinea pig detrusor with a pA2 value of 7.2. This activity, however, was unaffected by blockers of small and large conductance Ca-dependent K+ channels, such as apamin and charybdotoxin, respectively. The present study showed that Zeneca ZD6169 and its analog from the anilide tertiary carbinol series are K+ channel openers that activate KATP channels in vitro to relax bladder detrusors.
Databáze: OpenAIRE
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