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Ether and Carbamate Derivatives of 3-quinuclidinol and 3- hydroxymethylquinuclidine: Synthesis and Evaluation as Nicotinic Ligands

[ Vol. 12 , Issue. 6 ]


Sivakumar Annadurai, Min Zhang, Jerome L. Gabriel, Merouane Bencheriff and Daniel J. Canney   Pages 574 - 584 ( 11 )


Background: A lead quinuclidine-based nicotinic ligand (EQA) served as the basis for the design of novel compounds. A new series of 3-substituted quinuclidines was designed, synthesized and evaluated as nicotinic ligands.

Methods: The goal was to improve affinity for nicotinic receptors in the CNS. Interatomic distance calculations were performed on the proposed compounds as well as, known nicotinic ligands. The proposed compounds were then synthesized, characterized and evaluated in in vitro assays as nicotinic receptor ligands.

Results: Compounds 9a and 9b were found to inhibit the specific binding of 3H-(S)-Nicotine with Ki values of 48 nM and 42 nM respectively, indicating high affinity interactions with the α4β 2 subtype. Data suggest that several compounds act as partial agonists at CNS receptors with an efficacy between 28 and 40% and are potent partial activators of human muscle type receptors ( α1β 1γδ ; Emax= 80% that of 100 µ M nicotine).

Conclusions: Together these results indicate a partial agonism at muscle type receptors (ca. 40%) with no significant activation of rat ganglion-type receptors (α 3β 4*: asterisk indicates potential additional subunit that could partner to form the ganglionic receptor). The partial agonism inducing dopamine release from striatal synaptosomes ( α4β 2α 6α 4β 2β 3, and/or α 6β 2β 3) suggest that these compounds may in addition be acting at the α4 β2 and/or the α 6β 3* receptors. The partial agonists reported herein are interesting nicotinic ligands worthy of further investigation.


3-substituted quinuclidines, nicotinic acetylcholine receptors (nAChRs), internuclear distance in nicotinic ligands, receptor subtype, partial agonists, CNS receptors.


Associate Professor of Medicinal Chemistry, Chair, Department of Pharmaceutical Sciences, Director of Graduate Studies, Temple University School of Pharmacy, USA.

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