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The behavioral and cardiovascular effects of nicotinic ligands designed from the epibatidine template
Author(s) -
Jutkiewicz Emily M,
Carroll F Ivy,
Woods James H
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1043.4
Subject(s) - epibatidine , nicotinic agonist , chemistry , pharmacology , neuroscience , nicotinic acetylcholine receptor , medicine , biology , biochemistry , receptor
Selective α4β2 nicotinic antagonists may have potential as smoking cessation agents by attenuating the reinforcing effects of nicotine without producing deleterious cardiovascular effects. We evaluated 3 novel epibatidine analogs, RTI‐98, RTI‐102, and RTI‐ 154, in behavioral assays as compared with the known α4β2 antagonist dihydro‐beta‐erythroidine (DHbE). In rats discriminating nicotine from saline, RTI‐102, but not RTI‐98 and RTI‐154, partially generalized to the discriminative effects of nicotine and decreased rates of responding. In discrimination experiments, DHbE produced parallel, rightward shifts in the nicotine dose effect curve, but RTI‐98 and RTI0154 produced rightward and downward shifts. RTI‐102 and RTI‐98 increased blood pressure similar to that produced by nicotine, whereas RTI‐154 and DHbE did not alter blood pressure or heart rate. These data reveal that 1) RTI‐102 is a partial agonist in vivo, 2) RTI‐98 and RTI‐154 act like insurmountable antagonists at α4β2 receptors, and 3) RTI102 and RTI‐98 may also have agonist actions at α3β4 nicotinic receptors. Overall, these data demonstrate that compounds with different nicotine receptor subtype selectivity and activity can be created from the epibatidine template. These studies were supported by the University of Michigan Tobacco Research Network (EMJ, JHW) and DA12001 (FIC).Compound X YRTI‐98 H Cl RTI‐102 NO 2 H RTI‐154 CH 3 SO 2 H