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Further evaluation of the tropane analogs of haloperidol

机译：氟哌啶醇的托烷类似物的进一步评估

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Previous work from our labs has indicated that a tropane analog of haloperidol with potent D2 binding but designed to avoid the formation of MPP+-like metabolites, such as 4-(4-chlorophenyl)-1-(4- (4-fluorophenyl)-4-oxobutyl)pyridin-1-ium (BCPP+) still produced catalepsy, suggesting a strong role for the D2 receptor in the production of catalepsy in rats, and hence EPS in humans. This study tested the hypothesis that further modifications of the tropane analog to produce compounds with less potent binding to the D2 receptor than haloperidol, would produce less catalepsy. These tests have now revealed that while haloperidol produced maximum catalepsy, these compounds produced moderate to low levels of catalepsy. Compound 9, with the least binding affinity to the D2R, produced the least catalepsy and highest Minimum Adverse Effective Dose (MAED) of the analogs tested regardless of their affinities at other receptors including the 5-HT1AR. These observations support the hypothesis that moderation of the D2 binding of the tropane analogs could reduce catalepsy potential in rats and consequently EPS in man.
机译：我们实验室的先前工作表明，氟哌啶醇的托烷类似物具有有效的D2结合作用，但旨在避免形成MPP +样代谢物，例如4-（4-氯苯基）-1-（4-（4-氟苯基）- 4-氧代丁基）吡啶-1-鎓（BCPP +）仍然会导致僵直，这表明D2受体在大鼠僵直产生中具有很强的作用，因此在人类中也具有EPS。这项研究检验了以下假说，即对托烷类似物的进一步修饰以产生与氟哌啶醇相比对D2受体的结合力更弱的化合物的僵直症会更少。这些测试现已表明，尽管氟哌啶醇可产生最大的僵住症，但这些化合物产生的中至低水平的僵住症。化合物9对D2R的结合亲和力最小，无论它们对包括5-HT1AR在内的其他受体的亲和力如何，产生的僵直症最少，而最高逆向有效剂量（MAED）最高。这些观察结果支持了这样的假说：适度地降低托烷类似物的D2结合可以降低大鼠的僵直症潜力，从而降低人类的EPS。

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