ZENECA ZD6169 AND ITS ANALOGS FROM A NOVEL SERIES OF ANILIDE TERTIARYCARBINOLS - IN-VITRO K-ATP CHANNEL OPENING ACTIVITY IN BLADDER DETRUSOR

The potassium (K+) channel opening activity of Zeneca ZD6169 and one o f its pyridylsulfonyl analogs from the anilide tertiary carbinol serie s was ascertained. Their mechanoinhibitory effects on the myogenic act ivity of the guinea pig bladder detrusor muscle were measured in a set of functional assays. Elevating the K+ concentration in the tissue ba th from 15 to 80 mmol/l increased the IC50 value of ZD6169 from 1.61 /- 0.22 to 223 +/- 37 mu mol/l. This result suggests that ZD6169 may a ct as a K+ channel opener. Similar to the prototypic ATP-sensitive K(K-ATP) channel opener cromakalim, the K+ channel openers from the ani lide tertiary carbinol series displayed stereoselective mechanoinhibit ory activity only in the test protocol in which the detrusor was stimu lated with 15 mmol/l KCl. Being the active enantiomer, ZD6169 has an a ctivity more than 30-fold higher than the less active enantiomer. ZD61 69 at 10 mu mol/l hyperpolarized the guinea pig detrusor membrane pote ntial by 6.1 +/- 1.2 mV and increased the whole cell K-ATP current in isolated guinea pig smooth muscle cells by 34.9 +/- 7.9 pA. This is co mparable to the increase of 26.8 +/- 5.0 pA obtained with 10 mu mol/l of lemakalim, the active enantiomer of cromakalim. The K+ channel open ing activity of ZD6169 and the pyridylsulfonyl analog was competitivel y antagonized by the K-ATP channel blocker glibenclamide in the guinea pig detrusor with a pA(2) value of 7.2. This activity, however, was u naffected by blockers of small and large conductance Ca-dependent K+ c hannels, such as apamin and charybdotoxin, respectively. The present s tudy showed that Zeneca ZD6169 and its analog from the anilide tertiar y carbinol series are K+ channel openers that activate K-ATP channels in vitro to relax bladder detrusors.