N+/Si replacement as a tool for probing the pharmacophore of allosteric modulators of muscarinic M2 receptors:: Synthesis, allosteric potency, and positive cooperativity of silicon-based W84 derivatives

W84 (1) is an allosteric agent for the "common allosteric site" of muscarinic M-2 receptors, its allosteric action being characterized by an inhibition of [H-3]N-methylscopolamine ([H-3]NMS) dissociation. A series of silicon-based derivatives of 1 (compounds 2-7) were synthesized and studied for their allosteric interaction with porcine heart muscarinic M-2 receptors. Compound 2 (2-fold isosteric N+/Si exchange in the molecular framework of 1) and compounds 3-7 (single isosteric N+/Si exchange, varying (CH2)(n) chain length (n = 4-8) between the N and Si atom) were prepared by two-step (2) or four-step (3-7) syntheses, starting from ClSiMe2H (synthesis of 2) or ClSiMe2(CH2)(3)Cl (syntheses of 3-7). The identities of 2-7 were established by elemental analyses (C, H, N), NMR studies (H-1, C-13, N-15, Si-29), and MS experiments. In addition, the solvate 3(.)MeC(O)Me was structurally characterized by single-crystal X-ray diffraction. The electrostatically neutral compound 2 did not interfere with the muscarinic M-2 receptors, whereas the dicationic agent W84 (1) and the monocationic derivatives 3-7 inhibited [H-3]NMS dissociation. W84 (1) decreased [H-3]NMS equilibrium binding (negative cooperativity), whereas the silicon compound 5 enhanced [H-3]NMS equilibrium binding (positive cooperativity); i.e., exchange of one positively charged nitrogen atom in 1 by a silicon atom switched the allosteric action from negative to positive cooperativity. The silicon compounds 3, 4, and 6 enhanced [H-3]NMS equilibrium binding as well, whereas 7 behaved similarly to W84 (1).