LIGANDS FOR BRAIN CHOLINERGIC CHANNEL RECEPTORS - SYNTHESIS AND IN-VITRO CHARACTERIZATION OF NOVEL ISOXAZOLES AND ISOTHIAZOLES AS BIOISOSTERIC REPLACEMENTS FOR THE PYRIDINE RING IN NICOTINE

Ligands which activate neuronal nicotinic acetylcholine receptors (nAC hRs) represent a potential approach for the palliative treatment for t he symptoms of memory loss associated with Alzheimer's disease(AD). Ba sed upon this approach, a series of novel 3,5-disubstituted isoxazoles and isothiazoles were prepared and evaluated in vitro as cholinergic channel activators (ChCAs) of neuronal nAChRs. Many of the 3-substitut ed 5-(2-pyrrolidinyl)isoxazoles were found to have nanomolar binding a ffinities comparable to (S)-nicotine (2a) in a preparation of whole ra t brain. However, in a paradigm measuring the evoked release of [H-3]d opamine from a preparation of rat striatum, there were differences in the agonist potencies and efficacies of these analogues relative to 2a . The differences in agonist potency observed between compounds of com parable binding potency may be due to differences in ligand interactio ns with various subtypes of neuronal nAChRs.