Firestone J A, Gerhardt G A, DeBernardis J F, McKelvy J F, Browning M D
Department of Pharmacology, University of Colorado Health Sciences Center, Denver.
J Pharmacol Exp Ther. 1993 Mar;264(3):1206-10.
The balance between catecholamine (CA) release and reuptake is closely regulated and determines the effective level of transmitter at the synaptic cleft. Drugs that block CA uptake have potential utility as antidepressant medications. One such drug is racemic (+/-)-(1' R*,3R*)-3-phenyl-1-[1',2',3',4'-tetrahydro-5',6'- methylenedioxy-1'-naphthalenyl-methyl]-pyrrolidine methanesulfonate (A-7500), a novel polycyclic compound developed at Abbott Laboratories. This compound is known to bind to CA transporters in the central nervous system, however, its effects on an intact neurosecretory system have not been studied. In this regard, norepinephrine (NE) release from bovine adrenal chromaffin cells (BACC) is a classic model system for CA release and is an excellent system in which to examine the effects of drugs which modulate neurotransmitter release. We compared the effects of A-75200 and its two constituent enantiomers, A-74111 and A-74112, to the effects of three well-characterized uptake inhibitors, desipramine (DMI), nomifensine and cocaine. We found that the Abbott compounds inhibit [3H]norepinephrine ([3H]NE) uptake with an EC50 comparable to cocaine. In addition, unlike nomifensine and cocaine, these compounds inhibited nicotine- and K(+)-stimulated NE release, whereas histamine-stimulated release was preserved. Thus, the Abbott compounds block the effects on secretion of two agonists (nicotine and K+) which depend on a depolarization-dependent influx of extracellular calcium. We conclude that in addition to blocking NE uptake by inhibiting the NE transporter, the Abbott compounds may modulate peripheral NE release by inhibiting calcium flux through voltage-gated channels. This study demonstrates the utility of bovine adrenal chromaffin cells for preclinical trials of drugs that affect catecholaminergic neurotransmission.
儿茶酚胺（CA）释放与再摄取之间的平衡受到严格调控，并决定了突触间隙处递质的有效水平。阻断CA摄取的药物具有作为抗抑郁药物的潜在效用。其中一种药物是外消旋（+/-）-（1'R*，3R*）-3-苯基-1-[1'，2'，3'，4'-四氢-5'，6'-亚甲基二氧基-1'-萘基甲基]-吡咯烷甲磺酸盐（A-7500），这是雅培实验室研发的一种新型多环化合物。已知该化合物可与中枢神经系统中的CA转运体结合，然而，其对完整神经分泌系统的影响尚未得到研究。在这方面，牛肾上腺嗜铬细胞（BACC）释放去甲肾上腺素（NE）是CA释放的经典模型系统，也是研究调节神经递质释放药物作用的极佳系统。我们比较了A-75200及其两种对映体A-74111和A-74112与三种特征明确的摄取抑制剂地昔帕明（DMI）、诺米芬辛和可卡因的作用。我们发现雅培的这些化合物抑制[3H]去甲肾上腺素（[3H]NE）摄取的半数有效浓度（EC50）与可卡因相当。此外，与诺米芬辛和可卡因不同，这些化合物抑制尼古丁和K（+）刺激的NE释放，而组胺刺激的释放则得以保留。因此，雅培的这些化合物阻断了两种激动剂（尼古丁和K+）对分泌的影响，这两种激动剂依赖于细胞外钙的去极化依赖性内流。我们得出结论，除了通过抑制NE转运体来阻断NE摄取外，雅培的这些化合物可能通过抑制电压门控通道的钙内流来调节外周NE释放。这项研究证明了牛肾上腺嗜铬细胞在影响儿茶酚胺能神经传递药物的临床前试验中的效用。
