Department of Pharmaceutical Chemistry, Hamdard University, Hamdard Nagar, New Delhi, India.
Arch Pharm (Weinheim). 2012 Mar;345(3):185-94. doi: 10.1002/ardp.201100140. Epub 2011 Oct 14.
Various 1-[6-(4-substituted phenyl)-3-cyano-4-(substituted phenyl)-pyridin-2-yl]-5-oxopyrrolidine-3-carboxylic acids (3a-t) were designed and synthesized by clubbing pyrrolidinones and pyridines, the two active anticonvulsant pharmacophores. All the synthesized compounds fulfilled the requirements of suggested pharmacophoric model for anticonvulsant activity. Their in vivo anticonvulsant evaluation was performed by maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) tests. The minimal motor impairment was assessed by rotorod test and the estimation of various liver enzymes was performed to check the magnitude of liver toxicity posed by the synthesized compounds. Compounds 3d and 3k displayed comparable anticonvulsant activity to the standard drugs with ED(50) values of 13.4 and 18.6 mg/kg in electroshock screen, repectively. The compounds 3d and 3k were also found to have encouraging anticonvulsant activity (ED(50) = 86.1 and 271.6 mg/kg, respectively) in scPTZ screen. Interestingly, they did not show any sign of motor impairment at the maximum dose administered and were not toxic to the liver.
设计并合成了各种 1-[6-(4-取代苯基)-3-氰基-4-(取代苯基)-吡啶-2-基]-5-氧代吡咯烷-3-羧酸（3a-t），将吡咯烷酮和吡啶这两种具有活性的抗惊厥药效团结合在一起。所有合成的化合物都满足建议的抗惊厥活性药效团模型的要求。通过最大电休克惊厥（MES）和皮下戊四氮（scPTZ）试验进行体内抗惊厥评估。通过转棒试验评估最小运动障碍，并评估各种肝酶的估计值，以检查合成化合物引起的肝毒性程度。化合物 3d 和 3k 在电休克筛选中显示出与标准药物相当的抗惊厥活性，ED（50）值分别为 13.4 和 18.6mg/kg。还发现化合物 3d 和 3k 在 scPTZ 筛选中具有令人鼓舞的抗惊厥活性（ED（50）分别为 86.1 和 271.6mg/kg）。有趣的是，它们在给予的最大剂量下没有任何运动障碍的迹象，并且对肝脏没有毒性。
