DESIGN, SYNTHESIS, AND PHARMACOLOGICAL EVALUATION OF A SERIES OF NOVEL, GUANIDINE AND AMIDINE-CONTAINING NEONICOTINOID-LIKE ANALOGS OF NICOTINE: SUBTYPE-SELECTIVE INTERACTIONS AT NEURONAL NICOTINIC-ACETYLCHOLINE RECEPTOR.

Author

Aaron Joseph Haubner, University of KentuckyFollow

Date Available

12-14-2011

Year of Publication

2008

Degree Name

Doctor of Philosophy (PhD)

Document Type

Dissertation

College

Pharmacy

Department

Pharmaceutical Sciences

First Advisor

Dr. Peter A. Crooks

Abstract

The current project examined the ability of a novel series of guandine and amidine-containing nicotine analogs to interact with several native and recombinantlyexpressed mammalian neuronal nicotinic-acetylcholine receptor (nAChR) subtypes. Rational drug design methods and parallel organic synthesis was used to generate a library of guanidine-containing nicotine (NIC) analogs (AH compounds). A smaller series of amidine-containing nicotine analogs (JC compounds) were also synthesized. In total, >150 compounds were examined. Compounds were first assayed for affinity in a high-throughput [³H]epibatidine radioligand-binding screen. Lead compounds were evaluated in subtype-selective binding experiments to probe for affinity at the α₄β₂* and α₇* neuronal nAChRs. Several compounds were identified which possess affinity and selectivity for the α₄β₂* subtype [AH-132 (K_i=27nm) and JC-3-9 (K_i=11nM)]. Schild analysis of binding suggests a complex one-site binding interaction at the desensitized high-affinity nAChR. Whole-cell functional fluorescence (FLIPR) assays revealed mixed subtype pharmacology. AH-compounds were identified which act as activators and inhibitors at nAChR subtypes, while lead JC-compounds were found which possess full agonist activity at α₄β₂* and α₃β₄* subtypes. Compounds were identified as partial agonists, full agonists and inhibitors of multiple nAChR subtypes. Several SAR-based, ligand-receptor pharmacophore models were developed to guide future ligand design. Second-generation lead compounds were identified.

Recommended Citation

Haubner, Aaron Joseph, "DESIGN, SYNTHESIS, AND PHARMACOLOGICAL EVALUATION OF A SERIES OF NOVEL, GUANIDINE AND AMIDINE-CONTAINING NEONICOTINOID-LIKE ANALOGS OF NICOTINE: SUBTYPE-SELECTIVE INTERACTIONS AT NEURONAL NICOTINIC-ACETYLCHOLINE RECEPTOR." (2008). University of Kentucky Doctoral Dissertations. 621.
https://uknowledge.uky.edu/gradschool_diss/621