Samanin R, Caccia S, Bendotti C, Borsini F, Borroni E, Invernizzi R, Pataccini R, Mennini T
Psychopharmacology (Berl). 1980;68(1):99-104. doi: 10.1007/BF00426657.
4-(3-Indolyl-2-ethyl) piperidine (LM 5008), 2-(1-piperazinyl) quinoline (quipazine), and metachlorophenylpiperazine (mCPP) were studied for their ability to affect serotonergic mechanisms in vitro. Their relative potency in inhibiting serotonin (5-HT) uptake in vivo and reducing food intake in rats was also examined. mCPP was very potent in displacing 3H-5-HT bound to brain membranes (IC50, 6.2 X 10(-7) M), followed by quipazine, which showed an IC50 of 3.8 X 10(-6) M. LM 5008 was the least effective with an IC50 of 3.6 X 10(-5) M. mCPP and quipazine were less potent than d-fenfluramine in releasing 14C-5-HT from brain synaptosomes, while LM 5008 caused no significant effects at a concentration of 10(-5) M. Conversely, both in vitro and in vivo studies on 5-HT uptake showed that LM 5008 was the most potent compound in inhibiting 5-HT uptake and mCPP the least potent. Since a 50% reduction of food intake was not reached even with a dose of LM 5008 27-times higher than the ED50 for inhibiting 5-HT uptake in vivo, it is suggested that even marked inhibition of 5-HT uptake at central synapses is not sufficient per se to trigger serotonin-dependent anorexia in the rat. Increased release and/or direct stimulation of post-synaptic receptors may be necessary to obtain this effect. This could be of interest for developing new agents which can cause anorexia by interacting with brain serotonin.
研究了4-(3-吲哚基-2-乙基)哌啶（LM 5008）、2-(1-哌嗪基)喹啉（喹哌嗪）和间氯苯哌嗪（mCPP）影响体外5-羟色胺能机制的能力。还检测了它们在体内抑制5-羟色胺（5-HT）摄取及减少大鼠食物摄入量方面的相对效力。mCPP在置换与脑膜结合的3H-5-HT方面非常有效（半数抑制浓度[IC50]为6.2×10⁻⁷M），其次是喹哌嗪，其IC50为3.8×10⁻⁶M。LM 5008效果最差，IC50为3.6×10⁻⁵M。在从脑突触体释放14C-5-HT方面，mCPP和喹哌嗪的效力低于d-芬氟拉明，而LM 5008在10⁻⁵M浓度时无显著作用。相反，对5-HT摄取的体外和体内研究均表明，LM 5008是抑制5-HT摄取最有效的化合物，mCPP最无效。由于即使给予比体内抑制5-HT摄取的半数有效剂量（ED50）高27倍的LM 5008剂量，也未达到食物摄入量减少50%的效果，因此提示即使在中枢突触处显著抑制5-HT摄取本身也不足以引发大鼠的5-羟色胺依赖性厌食。可能需要增加5-羟色胺释放和/或直接刺激突触后受体才能产生这种效果。这对于开发可通过与脑5-羟色胺相互作用引起厌食的新药物可能具有重要意义。
