Klunk W E, Covey D F, Ferrendelli J A
Mol Pharmacol. 1982 Sep;22(2):438-43.
Derivatives of gamma-butyrolactone (GBL) substituted on the alpha- and/or gamma-positions were synthesized and tested for their effects on behavior in mice, on the electroencephalographs and blood pressure of paralyzed-ventilated guinea pigs, and on electrical activity of incubated hippocampal slices. Several compounds, including alpha-ethyl-alpha-methyl GBL (alpha-EMGBL), alpha, alpha-dimethyl GBL, alpha, gamma-diethyl-alpha, gamma-dimethyl GBL, and gamma-ethyl-gamma-methyl GBL, prevented seizures induced by pentylenetetrazol, beta-ethyl-beta-methyl-gamma-butyrolactone (beta-EMGBL), picrotoxin, or all three compounds in mice and guinea pigs but had no effect on seizures induced by maximal electroshock or bicuculline. Neither gamma-hydroxybutyrate (GHB) nor alpha-isopropylidine GBL had any anticonvulsant activity. The anticonvulsant alpha-substituted compounds had a potent hypotensive effect and antagonized the hypertensive effect of beta-EMGBL, alpha-EMGBL was tested in incubated hippocampal slices and was found to depress basal activity and antagonize excitation induced by beta-EMGBL. These results demonstrate that alpha-alkyl-substituted GBL and, to a lesser extent, gamma-substituted derivatives are anticonvulsant agents and that their effects are strikingly different from those of GHB or beta-alkyl-substituted GBLs, which are epileptogenic. Possibly beta- and alpha-substituted GBLs act at the same site as agonists and antagonists, respectively.
合成了在α和/或γ位被取代的γ-丁内酯（GBL）衍生物，并测试了它们对小鼠行为、对麻痹通气豚鼠的脑电图和血压以及对培养海马切片电活动的影响。几种化合物，包括α-乙基-α-甲基GBL（α-EMGBL）、α，α-二甲基GBL、α，γ-二乙基-α，γ-二甲基GBL和γ-乙基-γ-甲基GBL，可预防小鼠和豚鼠中由戊四氮、β-乙基-β-甲基-γ-丁内酯（β-EMGBL）、印防己毒素或这三种化合物共同诱导的癫痫发作，但对最大电休克或荷包牡丹碱诱导的癫痫发作没有影响。γ-羟基丁酸（GHB）和α-异亚丙基GBL均无抗惊厥活性。具有抗惊厥作用的α-取代化合物具有强效降压作用，并拮抗β-EMGBL的升压作用。对α-EMGBL在培养海马切片中进行了测试，发现其可抑制基础活动并拮抗β-EMGBL诱导的兴奋。这些结果表明，α-烷基取代的GBL以及程度较轻的γ-取代衍生物是抗惊厥剂，且它们的作用与致癫痫的GHB或β-烷基取代的GBL的作用明显不同。可能β-和α-取代的GBL分别作为激动剂和拮抗剂作用于同一部位。
