Relaxant activity in rat aorta and trachea, conversion to a muscarinic receptor antagonist and structure-activity relationships of new K-ATP activating 6-varied benzopyrans

To characterize ATP-sensitive channels (K-ATP channels) benzopyrans with di fferent substituents at position 6 were synthesized as new K-ATP-activators . Their relaxant potencies were determined in rat aorta and trachea. In aor ta, pEC(50)-values (-log, M) ranged from 7.37 to 5.43; in trachea, pEC(50)- values were 0.3 to 0.8 log units lower. Functional data were compared with binding data obtained in calf tracheal cells using the cyanoguanidine [H-3] P1075 (N-cyano-N'-1,1-dimethyl[2,3(n)-H-3]propyl)-N-11-(3-pyridinyl)guanidi ne) as radioligand. A high correlation (r = 0.96) between pEC(50)- and pK(D )-values indicated that tracheal relaxation produced by benzopyrans is medi ated via K-ATP channels without signal amplification. The permanently charg ed trimethylammonium derivative designed as a probe for the membrane site o f action completely lost its affinity for K-ATP channels, but converted to an antagonist for muscarinic acetylcholine receptors (pK(B) = 6.12 +/- 0.10 ), as confirmed in radioligand binding studies (pK(D) = 5.77 +/- 0.04). Str ucture-activity analyses revealed that the 6-substituent influences biologi cal activity by a direct receptor interaction of its own and not indirectly by withdrawing electrons from the benzopyran nucleus. The variance of the biological activity is primarily determined by electrostatic properties, bu t desolvation energies additionally contribute. (C) 1999 Elsevier Science B .V. All rights reserved.