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Vol. 299, Issue 1, 297-306, October 2001

SIB-1553A, (±)-4-{[2-(1-Methyl-2-pyrrolidinyl)ethyl]thio}phenol Hydrochloride, a Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors with Putative Cognitive-Enhancing Properties: Effects on Working and Reference Memory Performances in Aged Rodents and Nonhuman Primates

Bruno Bontempi1 , Kevin T. Whelan, Victoria B. Risbrough, Tadimeti S. Rao, Jerry J. Buccafusco, G. Kenneth Lloyd and Frédérique Menzaghi2

Merck Research Laboratories, La Jolla, California (B.B., K.T.W., V.B.R., T.S.R., G.K.L., F.M.); and Department of Pharmacology and Toxicology, Medical College of Georgia and Department of Veterans Affairs, Medical Center, Augusta, Georgia (J.J.B.)

Preclinical and clinical data have suggested the potential use of nicotinic acetylcholine receptor (nAChR) ligands for treating cognitive dysfunction associated with neurodegenerative diseases, such as Alzheimer's disease. SIB-1553A, (±)-4-{[2-(1-methyl-2-pyrrolidinyl)ethyl]thio}phenol hydrochloride, a novel nAChR ligand with predominant agonist subtype selectivity for beta 4 subunit-containing human neuronal nAChRs, was tested in a variety of cognitive paradigms in aged rodents and nonhuman primates after acute and repeated administration. Subcutaneous administration of SIB-1553A improved delayed nonmatching to place performance in aged mice. In aged rhesus monkeys, intramuscular and oral administration of SIB-1553A improved choice accuracy in a delayed matching to sample task. SIB-1553A improved performances in these spatial and nonspatial working memory tasks but was less effective at improving performances in spatial reference memory tasks (i.e., aged rodents exposed to a discrimination task in a T-maze or trained to locate a hidden platform in a water maze). These data suggest that SIB-1553A has a predominant effect on attention/working memory processes. SIB-1553A also induced the release of acetylcholine in the hippocampus of aged rats and was equally effective whether administered acutely or repeatedly (6 weeks of daily subcutaneous administration). Thus, rats repeatedly treated with SIB-1553A exhibit neither tolerance nor sensitization to the effects of the compound. The SIB-1553A-induced cognitive improvement may be in part related to an increase in cholinergic function. The present study provides additional support for the use of subtype-selective nAChR ligands as a potential therapy for the symptomatic treatment of specific cognitive deficits (such as attention/working memory deficits) associated with aging and neurological diseases.

1 Current address: Laboratoire de Neurosciences Cognitives, UMR CNRS 5106, Avenue des Facultés, 33405 Talence, France.

2 Current address: Arena Pharmaceuticals, Inc., 6166 Nancy Ridge Dr., San Diego, CA 92121.

0022-3565/01/2991-0297$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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