Gatley S J, Pan D, Chen R, Chaturvedi G, Ding Y S
Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
Life Sci. 1996;58(12):231-9. doi: 10.1016/0024-3205(96)00052-5.
We have synthesized several derivative of dl-threo-methylphenidate (Ritalin) bearing substituents on the phenyl ring. IC50 values for binding these compounds to rat brain monoamine transporters were assessed using [3H]WIN 35,428 (striatal membranes, dopamine transporters, DAT), [3H]nisoxetine (frontal cortex membranes, norepinephrine transporters, NET) and [3H]paroxetine (brain stem membranes, 5HT transporters, 5HTT). Affinities (1/Ki) decreased in the order: DAT > NET >> 5HTT. Substitution at the para position of dl-threo-methylphenidate generally led to retained or increased affinity for the dopamine transporter (bromo > iodo > methoxy > hydroxy). Substitution at the meta position also increased affinity for the DAT (m-bromo > methylphenidate; m-iodo-p-hydroxy > p-hydroxy). Substitution at the ortho position with bromine considerably decreased affinity. Similar IC50 values for binding of o-bromomethylphenidate to the dopamine transporter were measured at 0, 22 and 37 degrees. N-Methylation of the piperidine ring of methylphenidate also considerably reduced affinity. The dl-erythro isomer of o-bromomethylphenidate did not bind to the DAT (IC50 > 50,000 nM). Affinities at the dopamine and norepinephrine transporters for substituted methylphenidate derivatives were well correlated (r2=0.90). Abilities of several methylphenidate derivatives to inhibit [3H]dopamine uptake in striatal synaptosomes corresponded well with inhibition of [3H]WIN 35, 428 binding. None of the compounds examined exhibited significant affinity to dopamine D1 or D2 receptors (IC50 > 500 or 5,000 nM, respectively), as assessed by inhibition of binding of [3H]SCH 23390 or [123I]epidepride, respectively, to striatal membranes.
我们合成了几种在苯环上带有取代基的dl-苏式-甲基苯丙胺（利他林）衍生物。使用[3H]WIN 35,428（纹状体膜，多巴胺转运体，DAT）、[3H]去甲替林（额叶皮质膜，去甲肾上腺素转运体，NET）和[3H]帕罗西汀（脑干膜，5-羟色胺转运体，5HTT）评估了这些化合物与大鼠脑单胺转运体结合的IC50值。亲和力（1/Ki）按以下顺序降低：DAT > NET >> 5HTT。dl-苏式-甲基苯丙胺对位取代通常导致对多巴胺转运体的亲和力保持或增加（溴 > 碘 > 甲氧基 > 羟基）。间位取代也增加了对DAT的亲和力（间溴 > 甲基苯丙胺；间碘对羟基 > 对羟基）。邻位用溴取代大大降低了亲和力。在0、22和37摄氏度下测量了邻溴甲基苯丙胺与多巴胺转运体结合的类似IC50值。甲基苯丙胺哌啶环的N-甲基化也大大降低了亲和力。邻溴甲基苯丙胺的dl-赤式异构体不与DAT结合（IC50 > 50,000 nM）。取代甲基苯丙胺衍生物对多巴胺和去甲肾上腺素转运体的亲和力具有良好的相关性（r2 = 0.90）。几种甲基苯丙胺衍生物抑制纹状体突触体中[3H]多巴胺摄取的能力与抑制[3H]WIN 35,428结合的能力相当。通过分别抑制[3H]SCH 23390或[123I]表哌立登与纹状体膜的结合评估，所检测的化合物均未表现出对多巴胺D1或D2受体的显著亲和力（IC50分别 > 500或5,000 nM）。
