PARTIAL GABA(A) RECEPTOR AGONISTS - SYNTHESIS AND IN-VITRO PHARMACOLOGY OF A SERIES OF NONANNULATED ANALOGS OF 4,5,6,7-TETRAHYDROISOXAZOLO[5,4-C]PYRIDIN-3-OL

5-(4-Piperidyl)isoxazol-3-ol (4-PIOL, 10), a structural analog of 4-am inobutanoic acid (GABA, 1) and the GABAA agonist 4,5,6,7-tetrahydroiso xazolo[5,4-c]pyridin-3-ol (THIP, 5), is a low-efficacy partial GABA(A) agonist. A number of compounds bioisosterically derived from 10, incl uding 5-(4-piperidyl)isothiazol-3-ol (11), 3-(4-piperidyl)isoxazol-5-o l (12), 5-(1,2,3,6-tetrahydropyrid-4-yl)isoxazol-3-ol (13), and 5-(1,2 ,3,6-tetrahydropyrid-4-yl)isothiazol-3-ol (14), were synthesized and t ested as GABA(A) receptor ligands. Whereas none of these compounds sig nificantly affected GABA(B) receptor binding or GABA uptake, they show ed affinities for GABA(A) receptor sites in the low-micromolar range. Using cultured cerebral cortical neurons and whole-cell patch-clamp te chniques, the efficacies of these compounds relative to that of the fu ll GABA(A) agonist, isoguvacine (8) (20 mu M), were determined. The re lative efficacy of 11, which has a higher receptor affinity (IC50 = 1 3 +/- 0.3 mu M) than 10 (IC50 = 9 3 +/- 2.6 mu M), was comparable with that of 10 (30-35%). The tetrahydropyridine analog of 10, compound 13 , showed a markedly lower receptor affinity (IC50 = 32 +/- 10 mu M) an d apparently a lower relative efficacy than 10. The corresponding unsa turated analog of 11, compound 14, showed a slightly weaker receptor a ffinity (IC50 = 4.0 +/- 2.0 mu M) but a significantly higher relative efficacy (50-55%) than 11. The 5-isoxazolol isomer of 10, compound 12, showed a reduced receptor affinity (IC50 = 26 +/- 7 mu M) and a very low relative efficacy. Substitution of propanoic or propenoic acid moi eties for the acidic heterocyclic units of these compounds gave the mo nocyclic amino acids 15-18, which have very little or no affinity for GABA(A) receptor sites.