Synthesis and functional characterization of novel derivatives related to oxotremorine and oxotremorine-M.
ABSTRACT Two subseries of nonquaternized (5a-10a) and quaternized derivatives (5b-10b) related to oxotremorine and oxotremorine-M were synthesized and tested. The agonist potency at the muscarinic receptor subtypes of the new compounds was estimated in three classical in vitro functional assays: M1 rabbit vas deferens, M2 guinea pig left atrium and M3 guinea pig ileum. In addition, the occurrence of central muscarinic effects was evaluated as tremorigenic activity after intraperitoneal administration in mice. In in vitro tests a nonselective muscarinic activity was exhibited by all the derivatives with potencies values that, in some instances, surpassed those of the reference compounds (i.e. 8b). Functional selectivity was evidenced only for the oxotremorine-like derivative 9a, which behaved as a mixed M3-agonist/M1-antagonist (pD2 = 5.85; pA2 = 4.76, respectively). In in vivo tests non-quaternary compounds were able to evoke central muscarinic effects, with a potency order parallel to that observed in vitro.
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ABSTRACT: Dualsteric ligands represent a novel mode of targeting G protein-coupled receptors (GPCRs). These compounds attach simultaneously to both, the orthosteric transmitter binding site and an additional allosteric binding area of a receptor protein. This approach allows the exploitation of favourable characteristics of the orthosteric and the allosteric site by a single ligand molecule. The orthosteric interaction provides high affinity binding and activation of receptors. The allosteric interaction yields receptor subtype-selectivity and, in addition, may modulate both, efficacy and intracellular signalling pathway activation. Insight into the spatial arrangement of the orthosteric and the allosteric site is far advanced in the muscarinic acetylcholine receptor, and the design of dualsteric muscarinic agonists has now been accomplished. Using the muscarinic receptor as a paradigm, this review summarizes the way from suggestive evidence for an orthosteric/allosteric overlap binding to the rational design and experimental validation of dualsteric ligands. As allosteric interactions are increasingly described for GPCRs and as insight into the spatial geometry of ligand/GPCR-complexes is growing impressively, the rational design of dualsteric drugs is a promising new approach to achieve fine-tuned GPCR-modulation.British Journal of Pharmacology 02/2010; 159(5):997-1008. · 5.07 Impact Factor
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ABSTRACT: Allosteric modulators of ligand-receptor interactions are found for a variety of receptors (Christopoulos, 2002). Allosteric agents attach to a binding site being topographically distinct from the site for conventional (orthosteric) agonists or antagonists. In the case of the muscarinic receptor, a huge selection of structurally divergent modulators has been described for different receptor subtypes (Mohr et al., 2003). Alkane-bisammonio-type compounds carrying lateral phthalimido substituents are known to have a high affinity for the common allosteric binding site of the muscarinic acetylcholine M2 receptor (mAChR M2), which is already occupied by the orthosteric antagonist N-methylscopolamine (NMS). The resulting allosteric inhibition of the dissociation of [3H]NMS from the M2 receptors in porcine cardiac homogenates served to indicate binding of the test compounds to the allosteric site. Additionally, allosteric modulators can strongly influence equilibrium binding of the orthosteric ligand: Its binding can be reduced, left unaltered or elevated, and encoded as negative, neutral, and positive cooperativity, respectively (Christopoulos and Kenakin, 2002). The cooperativity is strongly dependent on the pair of allosteric/orthosteric ligands and on the receptor subtype.Journal of Molecular Neuroscience 02/2006; 30(1-2):165-8. · 2.89 Impact Factor
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ABSTRACT: We present a new concept of partial agonism at G protein-coupled receptors. We demonstrate the coexistence of two functionally distinct populations of the muscarinic M2 receptor stabilized by one dynamic ligand, which binds in two opposite orientations. The ratio of orientations determines the cellular response. Our concept allows predicting and virtually titrating ligand efficacy, which opens unprecedented opportunities for the design of drugs with graded activation of the biological system.Nature Chemical Biology 11/2013; · 12.95 Impact Factor