Neuroscience Research Unit, Pfizer Global Research and Development, Eastern Point Rd., Groton, CT 06340, USA.
J Pharmacol Exp Ther. 2012 Jun;341(3):681-91. doi: 10.1124/jpet.112.192351. Epub 2012 Mar 9.
5-Hydroxytryptamine (5-HT)(4) receptor agonists reportedly stimulate brain acetylcholine (ACh) release, a property that might provide a new pharmacological approach for treating cognitive deficits associated with Alzheimer's disease. The purpose of this study was to compare the binding affinities, functional activities, and effects on neuropharmacological responses associated with cognition of two highly selective 5-HT(4) receptor agonists, prucalopride and 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-[3-(piperidin-1-yl)propyl]thieno[2,3-b]pyridine-5-carboxamide (PRX-03140). In vitro, prucalopride and PRX-03140 bound to native rat brain 5-HT(4) receptors with K(i) values of 30 nM and 110 nM, respectively, and increased cAMP production in human embryonic kidney-293 cells expressing recombinant rat 5-HT(4) receptors. In vivo receptor occupancy studies established that prucalopride and PRX-03140 were able to penetrate the brain and bound to 5-HT(4) receptors in rat brain, achieving 50% receptor occupancy at free brain exposures of 330 nM and 130 nM, respectively. Rat microdialysis studies revealed that prucalopride maximally increased ACh and histamine levels in the prefrontal cortex at 5 and 10 mg/kg, whereas PRX-03140 significantly increased cortical histamine levels at 50 mg/kg, failing to affect ACh release at doses lower than 150 mg/kg. In combination studies, donepezil-induced increases in cortical ACh levels were potentiated by prucalopride and PRX-03140. Electrophysiological studies in rats demonstrated that both compounds increased the power of brainstem-stimulated hippocampal θ oscillations at 5.6 mg/kg. These findings show for the first time that the 5-HT(4) receptor agonists prucalopride and PRX-03140 can increase cortical ACh and histamine levels, augment donepezil-induced ACh increases, and increase stimulated-hippocampal θ power, all neuropharmacological parameters consistent with potential positive effects on cognitive processes.
5-羟色胺（5-HT）（4）受体激动剂据报道可刺激大脑乙酰胆碱（ACh）释放，这种特性可能为治疗与阿尔茨海默病相关的认知缺陷提供一种新的药理学方法。本研究的目的是比较两种高度选择性 5-HT（4）受体激动剂普鲁卡必利和 6,7-二氢-4-羟基-7-异丙基-6-氧代-N-[3-（哌啶-1-基）丙基]噻吩并[2,3-b]吡啶-5-甲酰胺（PRX-03140）的结合亲和力、功能活性以及与认知相关的神经药理学反应的影响。在体外，普鲁卡必利和 PRX-03140 分别以 30 nM 和 110 nM 的 Ki 值与天然大鼠脑 5-HT（4）受体结合，并增加表达重组大鼠 5-HT（4）受体的人胚肾-293 细胞中的 cAMP 产生。体内受体占有率研究表明，普鲁卡必利和 PRX-03140 能够穿透大脑，并与大鼠大脑中的 5-HT（4）受体结合，游离脑暴露分别为 330 nM 和 130 nM 时达到 50%的受体占有率。大鼠微透析研究表明，普鲁卡必利在 5 和 10 mg/kg 时最大程度地增加前额叶皮质中的 ACh 和组胺水平，而 PRX-03140 则在 50 mg/kg 时显著增加皮质组胺水平，低于 150 mg/kg 的剂量则无法影响 ACh 释放。在联合研究中，普鲁卡必利和 PRX-03140 增强了多奈哌齐诱导的皮质 ACh 水平增加。在大鼠的电生理学研究中，两种化合物均在 5.6 mg/kg 时增加了脑干刺激海马θ 振荡的功率。这些发现首次表明，5-HT（4）受体激动剂普鲁卡必利和 PRX-03140 可以增加皮质 ACh 和组胺水平，增强多奈哌齐诱导的 ACh 增加，并增加刺激海马θ 功率，所有这些神经药理学参数都与对认知过程的潜在积极影响一致。
