Synthesis and in vitro pharmacology of novel heterocyclic muscarinic ligands.

Article Details

Citation

De Amici M, Conti P, Fasoli E, Barocelli E, Ballabeni V, Bertoni S, Impicciatore M, Roth BL, Ernsberger P, De Micheli C

Synthesis and in vitro pharmacology of novel heterocyclic muscarinic ligands.

Farmaco. 2003 Sep;58(9):739-48.

PubMed ID
13679167 [ View in PubMed
]
Abstract

A set of novel heterocyclic ligands (7a-9a, 7b-9b, and 9c) structurally related to oxotremorine 2 was designed, synthesized, and tested at muscarinic receptor subtypes. In the binding experiments at cloned hm1-5, the presence of the 2-methylimidazole/2-methyl-3-alkylimidazolium moiety in place of the pyrrolidine ring revealed, in derivatives 8a, 8b, and 9c, a moderate selectivity for some receptor subtypes. The functional in vitro assays yielded results that correlated closely to binding data. In general, on passing from agonists bearing the pyrrolidine moiety to their analogues carrying the 2-methylimidazole function, the overall pharmacological efficacy profile is shifted from agonism toward partial agonism. The insertion of the 2-methyl-3-alkylimidazolium moiety advances the effect such that the compounds are pure antagonists. Quite similarly, chiral 3-oxo-Delta(2)-isoxazoline (+/-)-10 behaved as a weak antagonist unable to discriminate the different muscarinic receptor subtypes.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
PirenzepineMuscarinic acetylcholine receptor M1Ki (nM)21.38N/AN/ADetails
TropicamideMuscarinic acetylcholine receptor M4Ki (nM)3.47N/AN/ADetails