In vitro characterisation of the muscarinic receptor partial agonist, sabcomeline, in rat cortical and heart membranes

We have investigated the pharmacology of the functionally selective muscari nic M-1 receptor partial agonist, sabcomeline [SB-202026 (R-(Z)-(+)-alpha-( methoxyamino)-1-azabicyclo[2.2.2] octane-3-acetonitrile)], in rat cortex an d heart using radioligand binding and functional studies. The Quinuclidinyl benzilate/Oxotremorine-M acetate ratio from radioligand binding studies su ggested that sabcomeline and xanomeline [3(3-hexyloxy-1,25-thiadiazol-4-yl) - 1,2,5,6-tetrahydro-1-methylpyridine] are muscarinic receptor partial agon ists in cortical and heart membranes. In [S-35]GTP gamma S binding studies in rat cortex, carbachol stimulated binding via muscarinic M-2/M-4 receptor s which could be blocked by sabcomeline with a pA(2) of 7.2. In rat heart m embranes, carbachol also stimulated [S-35]GTP gamma S binding studies throu gh muscarinic M-2 receptors. Sabcomeline caused a small stimulation of basa l [S-35]GTP gamma S binding in both rat and heart tissues. Sabcomeline did not stimulate phosphoinositide hydrolysis in rat cortical slices, but did b lock the muscarinic M-1 receptor-mediated response caused by carbachol with apparent pK(b) of 6.9. Xanomeline and milameline also had no effect on pho sphoinositide hydrolysis up to 100 mu M In adenylyl cyclase studies in rat atria, sabcomeline inhibited forskolin-stimulated adenylyl cyclase activity to a similar extent to that of carbachol, xanomeline and milameline. The p resent study, using the techniques of radioligand binding, supports previou s publications which have claimed that sabcomeline is a muscarinic receptor partial agonist. As expected, this study shows that the functional actions of this compound at muscarinic receptor subtypes and in different tissues will depend on receptor reserve. (C) 1999 Elsevier Science B.V. All rights reserved.