Structure-activity studies related to ABT-594, a potent nonopioid analgesic agent: Effect of pyridine and azetidine ring substitutions on nicotinic acetylcholine receptor binding affinity and analgesic activity in mice

Analogs of A-98593 ( 1) and its enantiomer ABT-594 ( 2) with diverse substituents on the pyridine ring were prepared and tested for affinity to nicotinic acetylcholine receptor binding sites in rat brain and for analgesic activity in the mouse hot plate assay. Numerous types of modifications were consistent with high affinity for [ 3H]cytisine binding sites. By contrast, only selected modifications resulted in retention of analgesic potency in the same range as 1 and 2. Analogs of 2 with one or two methyl substituents at the 3-position of the azetidine ring also were prepared and found to be substantially less active in both assays. Analogs of A-98593 (R 1 = R 2 = H, ∗ = S , X = 6-Cl) and ABT-594 (R 1 = R 2 = H, ∗ = R , X = 6-Cl) were prepared and tested for affinity to nicotinic acetylcholine receptor binding sites in rat brain and for analgesic activity in the mouse hot plate assay.