AbstractLinopirdine (DuP 996) has been shown to enhance K+‐stimulated release of acetylcholine from cerebral cortex, striatum, and hippocampus of rats in vitro. X9121 is a structurally different compound identified as having similar release properties. The present experiments compare the effects of linopirdine and X9121 on cognitive deficits in aged rats, and on the pharmacological properties in young rats. For cognitive testing, aged male Fischer‐344 rats (24 months old, n = 116) received either vehicle or one of 5 doses of linopirdine or X9121 prior to behavioral testing; young rats (4 months old, n = 13) were controls and received vehicle prior to testing. Place discrimination and repeated acquisition were tested in the water maze, and a variety of sensorimotor tasks were given. Aging impaired performance in all tasks. Linopirdine (0.25, 2.5, and 8.5 mg/kg po [0.64, 7.4, and 25 μmol/kg]) and X9121 (0.85 and 8.5 mg/kg po [2.1 and 24 μmol/kg]) moderately improved place discrimination. None of the doses tested improved repeated acquisition or sensorimotor function. No behavioral indications of toxicity were observed. Acetylcholine release, acetylcholinesterase (AChE) inhibition, and nicotinic and muscarinic binding were measured in vitro in cerebral cortical tissue from young male Wistar rats (2 months old). Both linopirdine and X9121 enhanced K+‐stimulated release from cerebral cortex; X9121 produced greater release with a broader range of active concentrations. Linopirdine weakly inhibited AChE (1,000 × weaker than physostigmine) and X9121 did not. Neither drug bound significantly to muscarinic or nicotinic cholinergic receptors. These results support the hypothesis that linopirdine and X9121 have some cognition enhancing properties which may be due to enhancement of stimulation induced acetylcholine release. These results suggest that linopirdine and X9121 may be useful in treating disorders involving cognitive impairment. © 1994 Wiley‐Liss, Inc.