THE DESIGN OF NOVEL METHOCTRAMINE-RELATED TETRAAMINES AS MUSCARINIC RECEPTOR SUBTYPE-SELECTIVE ANTAGONISTS

Several novel methoctramine-related tetraamines were designed, and the ir biological profiles at muscarinic receptor subtypes were assessed b y functional experiments in isolated guinea pig and rat atria (M(2)) a nd smooth muscle (ileum and trachea, M(3)) and by binding assays in ra t cortex (M(1)), heart (M(2)), and submaxillary gland (M(3)) homogenat es and NG 108-15 cells (M(4)) Tripitramine, a nonsymmetrical tetraamin e, resulted in the most potent and the most selective muscarinic Mt re ceptor antagonist of the series (pA(2) = 9.14-9.85; pK(i) = 9.54). Spi rotramine (FC 15-94), a symmetrical tetraamine, was able to differenti ate between muscarinic M(1) receptors (pK(i) = 7.88) and the other sub types (M(2), pK(i) = 6.20; M(3), pK(i) = 5.81; M(4), PKi = 6.27). Thus , tripitramine and spirotramine could be valuable tools for the pharma cological classification and characterization of muscarinic receptor s ubtypes.