This K02 application proposes to provide me with release from teaching and administrative responsibilities and afford me a period of intensive research focus as a means of enhancing my research career. My career goal is to become a leading researcher in the field of drug abuse. In this application, I plan to develop a new class of subtype-selective nicotinic antagonists by determining the structure activity relationship (SAR) of pyridine-N substituted nicotine (NIC) analogues. Preliminary results demonstrate that N-octylnicotinium iodide (NONI) is a potent, selective, and competitive antagonist of NIC-evoked [3H]dopamine ([3H]DA) release. N-Decylnicotinium iodide (NDNI) competitively, and with high affinity, binds to the [3H]NIC binding site, but does not inhibit NIC-evoked [3H]DA release. These preliminary data demonstrate that pyridine-N substitution of the NIC molecule confers with nicotinic-receptor antagonist activity, and moreover, suggests that NONI and NDNI are selective for different nicotinic receptor subtypes. The proposed research will test the hypothesis that SAR directed at the pyridine-N substituent will optimize the potency, efficacy and nicotinic-receptor subtype selectivity of this novel class of nicotinic receptor antagonist. Structural modifications to be studied include varying pyridine-N substituent steric bulk and lipophilicity, alteration of C-2' chirality, enlargement of the pyrrolidine ring to a piperidine ring and rotameric preference about the C(3)-C(2') bond. The major goal of the research is to determine structural features of the novel NIC analogues that convert the NIC molecule from an agonist to an antagonist at specific nicotinic receptor subtypes. These subtype-selective nicotinic receptor antagonists would be invaluable neuropharmacologic agents for basic and clinical research. As evidence of Institutional support of this endeavor, I will be relieved of 75 percent of my teaching and committee assignments, and I will be provided with a postdoctoral research fellow and the work time and travel funds necessary to learn new techniques, including in vivo and in vitro electrochemistry from collaborative investigators at the University of Kentucky and Indiana University. Electrochemistry is a state-of-the-art technique which will provide outstanding spacial (within a brain region) and temporal resolution (msec) to measure neurotransmitter release both in the brain slice preparation and in the anesthetized, as well as awake and behaving animal. Thus, redistribution of my effort will allow me to concentrate on my research, including learning additional methodologies which will significantly extend my research capabilities and enhance my scientific career in drug abuse research.
