SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF PYRIDINE-MODIFIED ANALOGS OF 3-[2-((S)-PYRROLIDINYL)METHOXY]PYRIDINE, A-84543, A POTENT NICOTINIC ACETYLCHOLINE-RECEPTOR AGONIST

Analogs of 3-[2-((S)-pyrrolidinyl)methoxy]pyridine (A-84543, 1) with 2 -, 4-, 5-, and 6-substituents on the pyridine ring were synthesized. T hese analogs exhibited Ki values ranging from 0.15 to > 9,000 nM when tested in vitro for neuronal nicotinic acetylcholine receptor binding activity. Assessment of functional activity at subtypes of neuronal ni cotinic acetylcholine receptors indicates that pyridine substitution c an have a profound effect on efficacy at these subtypes, and several s ubtype-selective agonists and antagonists have been identified. (C) 19 98 Elsevier Science Ltd. All rights reserved.