Ligands for the common allosteric site of acetylcholine M2-receptors: development and application

Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M2 Receptor

“…Compound 23 , showing the fastest dissociation of the studied ligands ( 20 , 23 , and 28 ), was chosen to perform dissociation experiments in the presence of the allosteric M 2 R modulators W84 ( 32 ), − LY2119620 ( 33 ), , or alcuronium ( 34 ) , (for structures, see Figure S4, Supporting Information). The allosteric ligands, used at a high concentration of 100 μM, did not reduce the observed dissociation rate of 23 from the M 2 R as previously observed for the structurally related radioligands [ 3 H] 6 and [ 3 H] 7 .…”

“…4, Figure 7). These Supporting Information), [55][56][57] applied at increasing concentrations (Schild-like analysis, Figure 8). This kind of experiment is equivalent to the Schild analysis used to investigate the inhibiting effect of a receptor antagonist on the response elicited by an agonist, [62][63][64] and was applied, for instance, to prove the dualsteric binding mode of [ H]6 and [ 3 H]7 at the hM 2 R 38,39 as well as of a fluorescent pirenzepine derivative at the M 1 R. 31 In the presence of 32, the saturation isotherms of both monomeric ligands (20,23) and of the dimeric ligand 28 were rightward shifted resulting in linear 'Schild' regressions with a slope not different from unity (Figure 8; Table S1, Supporting Information).…”

The muscarinic system, cognition and schizophrenia

“…As a consequence it is very difficult to target a specific muscarinic receptor at this site without manipulating any of the remaining four receptors and producing unwanted side-effects and/or receptor down-regulation/drug desensitization (Lenz et al, 1994;Mirza et al, 2003;Mullaney et al, 1993;Thomas et al, 2009). Fortunately, it has been discovered that the M1 (Espinoza-Fonseca and Trujillo-Ferrara, 2005), M2 (Holzgrabe et al, 2000), M3 (Jooste et al, 2005), M4 (Kennedy et al, 2009) and M5 receptors all exhibit a secondary, allosteric binding site. Unlike the orthosteric binding sites, the allosteric binding sites demonstrate substantial heterogeneity across the five muscarinic receptors and thus have been the target for the more recently developed drugs.…”

Selective Activation of Muscarinic Acetylcholine Receptors for the Treatment of Schizophrenia

“…Significantly, allosteric sites have now been reported to be present on the muscarinic M1 [100], M2 [101], M3 [102], M4 [103] and M5 [104] receptors. Moreover, whilst the orthosteric agonist binding site seems to have been highly conserved across muscarinic receptors, the allosteric binding sites show considerable heterogeneity between receptors.…”