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PhD Thesis: Ryan Yoshimura

Dissertation Abstract:
Therapeutic Potential for Negative Allosteric Modulators of Nicotinic Acetylcholine Receptors

By Ryan Fusao Yoshimura
Doctor of Philosophy in Pharmacology and Toxicology
University of California, Irvine, 2008
Professor Kelvin W. Gee, Chair

In this dissertation the therapeutic potential for negative allosteric modulators of nicotinic acetylcholine receptors (nAChRs) is explored. The nAChRs are implicated as targets in a variety of disease states including nicotine addiction and disorders of affective states. These receptors also normally play a role in neuromuscular control, information gating, memory and cognition. Allosteric modulators are a class of drugs that have therapeutic advantages over competitive ligands due to their binding at a distinct site on the receptor. This dissertation describes the identification and characterization of a novel negative allosteric modulator of nAChRs, UCI-30002 and the evaluation of this mechanism as a potential treatment for nicotine addiction and depression.

The dissertation begins with the discovery and characterization of UCI-30002 as a non-selective inhibitor of neuronal nAChRs by oocyte electrophysiology. Further electrophysiological studies demonstrate a non-competitive and voltage-independent mechanism, indicating that UCI-30002 binds independently of the orthosteric ligand site and is outside the ion channel pore. UCI-30002 shows selectivity for the neuronal nAChR subtypes over the muscle nAChR subtype and is not significantly active at the GABAA and NMDA receptors tested.

The dissertation then describes the evaluation of UCI-30002 in an animal model of nicotine addiction, nicotine self-administration in rats. UCI-30002 reduces the reinforced responding for nicotine on both fixed ratio and progressive ratio schedules, but has no effect on responding for food reward on either schedule. Pharmacokinetic studies correlate the effective dose of UCI-30002 to an estimated brain concentration of 1mM, suggesting that ~30% inhibition of neuronal nAChR subtypes is sufficient to block nicotine self-administration.

The dissertation also evaluates UCI-30002 in an animal model of antidepressant-like activity, the tail suspension test in mice. UCI-30002 reduces immobility time in the tail suspension test at a dose that corresponds to ~80% inhibition of neuronal nAChR subtypes. The level of inhibition seen with UCI-30002 appears to correspond to the level of inhibition necessary for activity using mecamylamine.

The data presented support the hypothesis that negative allosteric modulation of neuronal nAChRs may be a viable mechanism to explore for potential pharmacotherapies for nicotine addiction and depression. This dissertation also begins to address the question of whether we can quantify a change in receptor function necessary to change an associated behavior.