Scott M K, Baxter E W, Bennett D J, Boyd R E, Blum P S, Codd E E, Kukla M J, Malloy E, Maryanoff B E, Maryanoff C A
R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477, USA.
J Med Chem. 1995 Oct 13;38(21):4198-210. doi: 10.1021/jm00021a009.
We recently reported on a series of pyrrole Mannich bases orally active in inhibiting the conditioned avoidance response (CAR) in rats. These compounds exhibit affinity for both D2 and 5-HT1A receptors, and some are noncataleptogenic. Such a profile suggests that they may be potential antipsychotic agents which lack the propensity for causing extrapyramidal side effects and tardive dyskinesias in humans. One of these compounds, 1-[[1-methyl-5-[[4-[2-(1-methylethoxy)phenyl]- 1-piperazinyl]methyl]-1H-pyrrol-2-yl]methyl]-2-piperidinone (RWJ 25730, 1), was chosen for further development but found to be unstable in dilute acid. In order to improve stability, we replaced the pyrrole methylene linkage to the piperazine ring with ethylene, employed ethylene and dicarbonyl as linkers between the lactam and the pyrrole ring, placed electron-withdrawing groups on the pyrrole ring, and substituted acyclic amide for lactam. In addition, we replaced the pyrrole segment with other heterocycles including thiophene, furan, isoxazole, isoxazoline, and pyridine. Generally, replacement of the N-methylpyrrole segment with thiophene, furan, isoxazoline, or pyridine afforded compounds equipotent with 1 in CAR, which were more stable in dilute acid. In the case of side chain or lactam modifications, CAR activity was significantly decreased or abolished, with the exception of 6. For the most part, the modifications to 1 resulted in the decrease or loss of D2 receptor binding. However, within this series, 5-HT1A receptor binding was greatly increased, with thiophene 40 exhibiting an IC50 of 0.07 nM. The CAR activities of pyrroles 6 and 12, thiophene 40, furans 44-47, isoxazolines 49 and 50, and pyridine 54 coupled with their weak or nonexistent D2 binding and strong 5-HT1A binding suggest that they may be acting via a nondopaminergic mechanism or that dopaminergic active metabolites are responsible. Pyrrole 6 and furans 44 and 47 show promise as antipsychotic agents based on their CAR activity, receptor-binding profile, and solution stability.
我们最近报道了一系列吡咯曼尼希碱，它们口服时能有效抑制大鼠的条件性回避反应（CAR）。这些化合物对D2和5-HT1A受体均具有亲和力，且有些无致僵性。这样的特性表明它们可能是潜在的抗精神病药物，在人类中不会引起锥体外系副作用和迟发性运动障碍。其中一种化合物，1-[[1-甲基-5-[[4-[2-(1-甲乙氧基)苯基]-1-哌嗪基]甲基]-1H-吡咯-2-基]甲基]-2-哌啶酮（RWJ 25730，1），被选作进一步研发，但发现其在稀酸中不稳定。为提高稳定性，我们将吡咯与哌嗪环之间的亚甲基连接换成乙烯，采用乙烯和二羰基作为内酰胺与吡咯环之间的连接基，在吡咯环上引入吸电子基团，并用无环酰胺取代内酰胺。此外，我们用包括噻吩、呋喃、异恶唑、异恶唑啉和吡啶在内的其他杂环取代了吡咯片段。一般来说，用噻吩、呋喃、异恶唑啉或吡啶取代N-甲基吡咯片段得到的化合物在CAR试验中与1等效，且在稀酸中更稳定。对于侧链或内酰胺修饰的情况，除6外，CAR活性显著降低或丧失。在大多数情况下，对1的修饰导致D2受体结合能力降低或丧失。然而，在该系列化合物中，5-HT1A受体结合能力大幅提高，噻吩40的IC50为0.07 nM。吡咯6和12、噻吩40、呋喃44 - 47、异恶唑啉49和50以及吡啶54的CAR活性，再加上它们较弱或不存在的D2结合以及较强的5-HT1A结合，表明它们可能通过非多巴胺能机制起作用，或者多巴胺能活性代谢产物起作用。基于其CAR活性、受体结合特性和溶液稳定性，吡咯6以及呋喃44和47有望成为抗精神病药物。
