M1 MUSCARINIC ANTAGONISTS INTERACT WITH SIGMA-RECOGNITION SITES

The M1-selective muscarinic antagonists aprophen, caramiphen, carbetapentane, 2-DAEX, dicyclomine, hexahydrosiladifenidol, iodocaramiphen, nitrocaramiphen, oxybutynin and trihexyphenidyl potently inhibited binding to sigma-sites in brain. Both basic ester and non-ester structural type compounds which exhibit affinity for the muscarinic receptor also demonstrated affinity for the sigma-site, while the classical antimuscarinic agents atropine and QNB, and the tricyclic pirenzepine, were ineffective in binding to this site. We also observed a significant correlation between the K(i) values for sigma-compounds to inhibit [H-3]pirenzepine binding and their IC50 values to inhibit carbachol-stimulated phosphoinositide turnover. These observations may aid in elucidating the relationship of sigma-binding to inhibition of phosphoinositide turnover stimulated by cholinergic agonists.