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 α4β2 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 (α1β1γδ; Emax= 80% that of 100 µM nicotine).
Conclusions: Together these results indicate a partial agonism at muscle type receptors (ca. 40%) with no significant activation
of rat ganglion-type receptors (α3β4*: asterisk indicates potential additional subunit that could partner to form the
ganglionic receptor). The partial agonism inducing dopamine release from striatal synaptosomes (α4β2α6α4β2β3, and/or
α6β2β3) suggest that these compounds may in addition be acting at the α4β2 and/or the α6β3* receptors. The partial agonists
reported herein are interesting nicotinic ligands worthy of further investigation.