A novel series of muscarinic receptor ligands of the hexamethonio-type was prepared which contained, on one side, the phthalimidopropane or 1,8-naphthalimido-2,2-dimethylpropane moiety typical for subtype selective allosteric antagonists and, on the other, the acetylenic fragment typical for the nonselective orthosteric muscarinic agonists oxotremorine, oxotremorine-M, and related muscarinic agonists. Binding experiments in M-2 receptors using [H-3]N-methylseopolamine as an orthosteric probe proved an allosteric action of both groups of hybrids, 7a-10a and 8b-10b. The difference in activity between a-group and b-group hybrids corresponded with the activity difference between the allosteric parent compounds. In M-1-M-3 muscarinic isolated organ preparations, most of the hybrids behaved as subtype selective antagonists. [S-35]GTP gamma S binding assays using human M-2 receptors overexpressed. in CHO cells revealed that a weak intrinsic efficacy was preserved in 8b-10b. Thus, attaching muscarinic allosteric antagonist moieties to orthosteric muscarinic agonists may lead to hybrid compounds in which functions of both components are mixed
Design, synthesis, and action of oxotremorine-related hybrid-type allosteric modulators of muscarinic acetylcholine receptors / T. DISINGRINI, M. MUTH, C. DALLANOCE, E. BAROCELLI, S. BERTONI, K. KELLERSHOHN, K. MOHR, M. DE AMICI, U. HOLZGRABE. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 49:1(2006), pp. 366-372.
Design, synthesis, and action of oxotremorine-related hybrid-type allosteric modulators of muscarinic acetylcholine receptors
T. DISINGRINIPrimo
;C. DALLANOCE;M. DE AMICIPenultimo
;
2006
Abstract
A novel series of muscarinic receptor ligands of the hexamethonio-type was prepared which contained, on one side, the phthalimidopropane or 1,8-naphthalimido-2,2-dimethylpropane moiety typical for subtype selective allosteric antagonists and, on the other, the acetylenic fragment typical for the nonselective orthosteric muscarinic agonists oxotremorine, oxotremorine-M, and related muscarinic agonists. Binding experiments in M-2 receptors using [H-3]N-methylseopolamine as an orthosteric probe proved an allosteric action of both groups of hybrids, 7a-10a and 8b-10b. The difference in activity between a-group and b-group hybrids corresponded with the activity difference between the allosteric parent compounds. In M-1-M-3 muscarinic isolated organ preparations, most of the hybrids behaved as subtype selective antagonists. [S-35]GTP gamma S binding assays using human M-2 receptors overexpressed. in CHO cells revealed that a weak intrinsic efficacy was preserved in 8b-10b. Thus, attaching muscarinic allosteric antagonist moieties to orthosteric muscarinic agonists may lead to hybrid compounds in which functions of both components are mixedPubblicazioni consigliate
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