The thio analogues of the GABA (gamma-aminobutyric acid) agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), the GABA uptake inhibitor THPO (4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol), and the glycine antagonist THAZ (5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol) have been synthesized and tested biologically on single neurons in the cat spinal cord and in vitro by using synaptic membrane preparations obtained from rat brains. In contrast to THIP, thio-THIP (4,5,6,7-tetrahydroisothiazolo[5,4-c]pyridin-3-ol, 5) was only a weak GABA agonist. Thio-THPO (4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol, 10) was slightly weaker than THPO as an inhibitor of GABA uptake in vitro, and these two compounds were approximately equipotent in enhancing the inhibition of the firing of cat spinal neurons by GABA. Like THAZ and structurally related bicyclic isoxazole zwitterions, thio-THAZ (5,6,7,8-tetrahydro-4H-isothiazolo[4,5-d]azepin-3-ol, 15) was an antagonist at glycine receptors on cat spinal neurons. The I/U ratios, which reflect the ability of neutral amino acids to penetrate the blood-brain barrier (BBB), were calculated for 5 (I/U = 16), 10 (63), and 15 (200). These low I/U ratios, compared with the findings that THIP (I/U = 500 or 1500) and THPO (I/U = 2500) enter the brain after systemic administration, suggest that the thio analogues may penetrate the BBB very easily.

中文翻译：

---

4,5,6,7-四氢异噻唑并[5,4-c]吡啶-3-醇及THIP的相关类似物。合成和生物活性。

GABA（γ-氨基丁酸）激动剂THIP（4,5,6,7-四氢异恶唑并[5,4-c] pyridin-3-ol），GABA摄取抑制剂THPO（4,5,6， 7-四氢异恶唑[4,5-c]吡啶-3-醇）和甘氨酸拮抗剂THAZ（5,6,7,8-四氢-4H-异恶唑[4,5-d] azepin-3-ol）具有通过使用从大鼠脑获得的突触膜制剂，合成并在猫脊髓中的单个神经元上进行了体外生物学测试，并在体外进行了测试。与THIP相反，硫代THIP（4,5,6,7-四氢异噻唑并[5,4-c]吡啶-3-醇，5）只是一种弱的GABA激动剂。作为体外GABA吸收抑制剂，Thio-THPO（4,5,6,7-四氢异噻唑并[4,5-c]吡啶-3-醇，10）略弱于THPO，并且这两种化合物在体内的作用大致相同。增强GABA对猫脊髓神经元放电的抑制作用。像THAZ和与结构相关的双环异恶唑两性离子一样，硫代THAZ（5,6,7,8-四氢-4H-异噻唑并[4,5-d] azepin-3-ol，15）是猫脊髓上甘氨酸受体的拮抗剂。神经元。计算出I / U比率分别为5（I / U = 16），10（63）和15（200），反映了中性氨基酸穿透血脑屏障（BBB）的能力。与全身给药后THIP（I / U = 500或1500）和THPO（I / U = 2500）进入大脑的发现相比，这些低的I / U比表明硫代类似物可能非常容易穿透BBB。计算了5个（I / U = 16），10（63）和15（200）。与全身给药后THIP（I / U = 500或1500）和THPO（I / U = 2500）进入大脑的发现相比，这些低的I / U比表明硫代类似物可能非常容易穿透BBB。计算了5个（I / U = 16），10（63）和15（200）。与全身给药后THIP（I / U = 500或1500）和THPO（I / U = 2500）进入大脑的发现相比，这些低的I / U比表明硫代类似物可能非常容易穿透BBB。