N + /Si Replacement as a Tool for Probing the Pharmacophore of Allosteric Modulators of Muscarinic M 2 Receptors: Synthesis, Allosteric Potency, and Positive Cooperativity of Silicon-Based W84 Derivatives
2002; American Chemical Society; Volume: 21; Issue: 5 Linguagem: Inglês
10.1021/om010847j
ISSN1520-6041
AutoresJ.O. Daiss, Seraina Duda‐Johner, Christian Burschka, Ulrike Holzgrabe, Klaus Mohr, Reinhold Tacke,
Tópico(s)Chemical Synthesis and Analysis
ResumoW84 (1) is an allosteric agent for the "common allosteric site" of muscarinic M2 receptors, its allosteric action being characterized by an inhibition of [3H]N-methylscopolamine ([3H]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 M2 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)3Cl (syntheses of 3−7). The identities of 2−7 were established by elemental analyses (C, H, N), NMR studies (1H, 13C, 15N, 29Si), 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 M2 receptors, whereas the dicationic agent W84 (1) and the monocationic derivatives 3−7 inhibited [3H]NMS dissociation. W84 (1) decreased [3H]NMS equilibrium binding (negative cooperativity), whereas the silicon compound 5 enhanced [3H]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 [3H]NMS equilibrium binding as well, whereas 7 behaved similarly to W84 (1).
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