Synthetic analgesics and other phenylpiperidines: effects on uptake and storage of dopamine and other monoamines mouse forebrain tissue.
Synthetic analgesics and other phenylpiperidines: effects on uptake and storage of dopamine and other monoamines mouse forebrain tissue.
复制标题
合成镇痛药和其他苯基哌啶：对多巴胺和其他单胺小鼠前脑组织的吸收和储存的影响。
DOI：
10.1016/0024-3205(86)90096-2
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发表时间：
1986
期刊：
影响因子：
6.1
通讯作者：
Neumeyer,JL
中科院分区：
文献类型：
--
作者：
Baldessarini,RJ;Kula,NS;Francoeur,D;Finklestein,SP;Murphy,F;Neumeyer,JL
神经毒素N-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）可引起人、猴和小鼠的多巴胺（DA）等中枢单胺神经元变性，导致帕金森病样效应。在小鼠纹状体或大脑皮层的突触体制备物中，评价MPTP和其他与合成镇痛剂（包括阿法罗定和哌替啶）相关的取代苯基哌啶的效力与0.1 μM氚化DA、去甲肾上腺素（NE）或5-羟色胺（5-HT）的摄取。MPTP代谢产物N-甲基-4-苯基吡啶离子（MPP+，IC_（50）= 1μM，Ki = 0.4μM）是~ 3 H-DA摄取的最强抑制剂，其作用是竞争性的，可逆的。MPTP的其他类似物：N-乙基吲哚AHR-1709、N，N-二甲基-MPTP和N-甲基-4-苯基哌啶对~ 3 H-DA摄取抑制作用均强于MPTP。N-脱烷基化和N-丙基取代以及吡啶环取代降低了对DA摄取的亲和力，而3′，4 ′-二羟基苯基取代增加了对儿茶酚胺摄取的效力和选择性，吡啶环的季铵化也增加了对DA摄取的效力。活性化合物对NE摄取的抑制效力高于DA。MPP+在从纹状体突触体释放内源性DA方面也比MPTP更有效（EC 50 = 3 vs. 30μM），但不释放细胞质标记物酪氨酸羟化酶和乳酸脱氢酶（LDH）。与MPTP相反，合成的苯基哌啶镇痛药，其潜在的代谢产物和实验性神经阻滞剂AHR-1709都未能在体内耗尽纹状体DA，即使在体外对DA摄取有活性。
The neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can induce degeneration of dopamine (DA) and other central monoamine neurons, leading to Parkinson's disease-like effects in man, monkey, and mouse. MPTP and other substituted phenylpiperidines related to synthetic analgesics including alphaprodine and meperidine were evaluated for potency vs. uptake of 0.1 μM tritiated DA, norepinephrine (NE), or serotonin (5HT) in synaptosomal preparations of mouse striatum or cerebral cortex. The most potent inhibitor of the uptake of3H-DA was N-methyl-4-phenylpyridinium ion (MPP+; IC50= 1μM, Ki = 0.4μM), a metabolite of MPTP; its effect was competitive and reversible. Other analogs of MPTP: the N-ethylindole AHR-1709, N,N-dimethyl-MPTP, and N-methyl-4-phenylpiperidine were all more potent than MPTP against3H-DA uptake. N-dealkylation and N-propyl substitution, as well as pyridine ring substitution, decreased affinity for DA uptake while 3′,4′-dihydroxyphenyl substitution increased potency and selectivity for catecholamine uptake, and quarternarization of the pyridine ring also increased potency against DA uptake. Active compounds showed higher potency against the uptake of NE than of DA. MPP+was also more potent than MPTP in releasing endogenous DA from striatal synaptosomes (EC50= 3 vs. 30μM), but did not release the cytoplasmic markers tyrosine hydroxylase and lactate dehydrogenase (LDH). In contrast to MPTP, synthetic phenylpiperidine analgesics, their potential metabolites and the experimental neuroleptic agent AHR-1709 all failed to deplete striatal DA in vivo, even if active in vitro against DA uptake.