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[摘要]：Drugs used to treat various disorders target GABAA receptors. To develop a subunit selective compds., we synthesized 5-(4-piperidyl)-3-isoxazolol (4-PIOL) derivs. The 3-isoxazolol moiety was substituted by 1,3,4-oxadiazol-2-one , 1,3,4-oxadiazol-2-thione, and substituted 1,2,4-triazol-3-one heterocycles, e.g. I (R = 4-piperidyl, 2-pyrrolidinyl, H2NCH2CH2, etc., X = O, S, Y = O; R = 4-piperidinyl, H2NCH2, X = O, S, Y = PhCH2N), with modifications to the basic piperidine substituent as well as substituents without basic nitrogen. Compds. were screened by [3H]muscimol binding and in patch-clamp expts. with heterologously expressed GABAA aib3g2 receptors (i = 1-6). The effects of 5-aminomethyl-3H-[1,3,4]oxadiazol-2-one were comparable to GABA for all a subunit isoforms. 5-Piperidin-4-yl-3H-[1,3,4]oxadiazol-2-one and 5-piperidin-4-yl-3H-[1,3,4]oxadiazol-2-thione (II) were weak agonists at a2-, a3-, and a5-contg. receptors. When coapplied with GABA, they were antagonistic in a2-, a4-, and a6-contg. receptors and potentiated a3-contg. receptors. II protected GABA binding site cysteine-substitution mutants a1F64C and a1S68C from reacting with methanethiosulfonate-ethylsulfonate. II specifically covalently modified the a1R66C thiol, in the GABA binding site, through its oxadiazolthione sulfur. These results demonstrate the feasibility of synthesizing a subtype selective GABA mimetic drugs. |
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