Carter C, Benavides J, Legendre P, Vincent J D, Noel F, Thuret F, Lloyd K G, Arbilla S, Zivkovic B, MacKenzie E T
Laboratories d'Etudes et de Recherches Synthélabo, Biology Department, Bagneux, France.
J Pharmacol Exp Ther. 1988 Dec;247(3):1222-32.
The effects of the anti-ischemic agents ifenprodil and its derivative SL 82.0715 ((+/-)-alpha-(4-chlorophenyl)-4-[(4-fluorophenyl) methyl]-1-piperidineethanol] have been analyzed in a number of models indicative of N-methyl-D-aspartate (NMDA) antagonistic potential in vitro and in vivo. Ifenprodil and SL 82.0715 potently and noncompetitively antagonize the stimulatory effects of NMDA on cyclic GMP production in immature rat cerebellar slices (IC50 values, 0.4 and 10 microM, respectively), as well as the NMDA-evoked [3H]acetylcholine release in adult rat striatal slices (IC50 values, 1.6 and 6.6 microM, respectively). Ifenprodil is 10 times more potent than (+/-)3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) but less active than the reference noncompetitive NMDA channel blockers [MK 801, ((+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine ], phencyclidine and 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP)] in these models. Ifenprodil and SL 82.0715 partially displace (maximal displacement 40-50% at 10 microM) the NMDA receptor ligand [3H]CPP from its binding site to rat brain membranes (IC50 values, 0.1 and 0.3 microM, respectively) in a noncompetitive manner; in the micromolar range the two agents also partially displace the NMDA channel ligand [3H]TCP from its binding site to rat brain membranes, and noncompetitively antagonize the L-glutamate-induced increase in [3H]TCP binding. Ifenprodil (0.01-1 microM) partially antagonizes the depolarizing effects of NMDA on the immature rat hemisected spinal cord in vitro. In mouse cultured spinal cord neurons, ifenprodil dose-dependently antagonizes the depolarizing effects of micropressure applied NMDA. Inhibition of the effects of NMDA in this model by ifenprodil and SL 82.0715 is noncompetitive. In vivo and after systemic i.p. administration, ifenprodil and SL 82.0715 antagonize the stimulatory effects of intrastriatally dialyzed NMDA on striatal dopamine release in rats (ID50 values, 0.9 and 0.3 mg/kg, respectively), and block the harmaline-evoked increase in cerebellar cyclic GMP production in mice (ID50 values, 3 and 4 mg/kg, respectively). These results indicate that ifenprodil is a noncompetitive NMDA antagonist which has a mechanism of action distinct from either the reference competitive NMDA receptor antagonists (CPP and 2-amino-5-phosphonovalerate) or the noncompetitive NMDA channel blockers (phencyclidine, TCP and MK 801). The potent NMDA antagonistic effects of the ifenprodil class of compounds are likely to be related to the demonstrated anti-ischemic potential of these compounds.
已在多种体外和体内模型中分析了抗缺血药物艾芬地尔及其衍生物SL 82.0715（(±)-α-(4-氯苯基)-4-[(4-氟苯基)甲基]-1-哌啶乙醇）的作用，这些模型可指示N-甲基-D-天冬氨酸（NMDA）的拮抗潜力。艾芬地尔和SL 82.0715能有效且非竞争性地拮抗NMDA对未成熟大鼠小脑切片中环鸟苷酸（cGMP）生成的刺激作用（IC50值分别为0.4和10 μM），以及NMDA诱发的成年大鼠纹状体切片中[3H]乙酰胆碱的释放（IC50值分别为1.6和6.6 μM）。在这些模型中，艾芬地尔的效力比(±)3-(2-羧基哌嗪-4-基)丙基-1-膦酸（CPP）强10倍，但比参考非竞争性NMDA通道阻滞剂[MK 801，((+)-5-甲基-10,11-二氢-5H-二苯并-[a,d]环庚烯-5,10-亚胺]、苯环己哌啶和1-[1-(2-噻吩基)环己基]哌啶（TCP）的活性低。艾芬地尔和SL 82.0715以非竞争性方式部分取代（在10 μM时最大取代率为40 - 50%）NMDA受体配体[3H]CPP与大鼠脑膜结合位点的结合（IC50值分别为0.1和0.3 μM）；在微摩尔范围内，这两种药物也部分取代NMDA通道配体[3H]TCP与大鼠脑膜结合位点的结合，并非竞争性地拮抗L-谷氨酸诱导的[3H]TCP结合增加。艾芬地尔（0.01 - 1 μM）部分拮抗NMDA对体外未成熟大鼠半切脊髓的去极化作用。在小鼠培养的脊髓神经元中，艾芬地尔剂量依赖性地拮抗微压力施加的NMDA的去极化作用。在该模型中，艾芬地尔和SL 82.0715对NMDA作用的抑制是非竞争性的。在体内经腹腔注射给药后，艾芬地尔和SL 82.0715拮抗纹状体内透析的NMDA对大鼠纹状体多巴胺释放的刺激作用（ID50值分别为0.
