Roche Palo Alto, Palo Alto, California (S.S., T.W., R.H., H.M., K.B., M.E.M., D.C.B.); F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Discovery Neuroscience, Grenzacherstrasse, Basel, Switzerland (F.K., L.S.); gRED South San Francisco, California (D.M.); HiQScreen Sarl, Geneva, Switzerland (D.B.); and Psychogenics Inc., Tarrytown, New York (G.C.T.).
Roche Palo Alto, Palo Alto, California (S.S., T.W., R.H., H.M., K.B., M.E.M., D.C.B.); F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Discovery Neuroscience, Grenzacherstrasse, Basel, Switzerland (F.K., L.S.); gRED South San Francisco, California (D.M.); HiQScreen Sarl, Geneva, Switzerland (D.B.); and Psychogenics Inc., Tarrytown, New York (G.C.T.)
J Pharmacol Exp Ther. 2014 Aug;350(2):455-68. doi: 10.1124/jpet.113.210963. Epub 2014 Jun 10.
Both preclinical evidence and clinical evidence suggest that α7 nicotinic acetylcholine receptor activation (α7nAChR) improves cognitive function, the decline of which is associated with conditions such as Alzheimer's disease and schizophrenia. Moreover, allosteric modulation of α7nAChR is an emerging therapeutic strategy in an attempt to avoid the rapid desensitization properties associated with the α7nAChR after orthosteric activation. We used a calcium assay to screen for positive allosteric modulators (PAMs) of α7nAChR and report on the pharmacologic characterization of the novel compound RO5126946 (5-chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide), which allosterically modulates α7nAChR activity. RO5126946 increased acetylcholine-evoked peak current and delayed current decay but did not affect the recovery of α7nAChRs from desensitization. In addition, RO5126946's effects were absent when nicotine-evoked currents were completely blocked by coapplication of the α7nAChR-selective antagonist methyl-lycaconitine. RO5126946 enhanced α7nAChR synaptic transmission and positively modulated GABAergic responses. The absence of RO5126946 effects at human α4β2nAChR and 5-hydroxytryptamine 3 receptors, among others, indicated selectivity for α7nAChRs. In vivo, RO5126946 is orally bioavailable and brain-penetrant and improves associative learning in a scopolamine-induced deficit model of fear conditioning in rats. In addition, procognitive effects of RO5126946 were investigated in the presence of nicotine to address potential pharmacologic interactions on behavior. RO5126946 potentiated nicotine's effects on fear memory when both compounds were administered at subthreshold doses and did not interfere with procognitive effects observed when both compounds were administered at effective doses. Overall, RO5126946 is a novel α7nAChR PAM with cognitive-enhancing properties.
临床前证据和临床证据都表明，α7 烟碱型乙酰胆碱受体激活（α7nAChR）可以改善认知功能，而认知功能的下降与阿尔茨海默病和精神分裂症等疾病有关。此外，α7nAChR 的变构调节是一种新兴的治疗策略，试图避免与α7nAChR 变构激活相关的快速脱敏特性。我们使用钙测定法筛选α7nAChR 的正变构调节剂（PAMs），并报告新型化合物 RO5126946（5-氯-N-[(1S,3R)-2,2-二甲基-3-(4-磺酰胺基-苯基)-环丙基]-2-甲氧基-苯甲酰胺）的药理特征，该化合物变构调节α7nAChR 活性。RO5126946 增加了乙酰胆碱诱发的峰值电流并延迟了电流衰减，但不影响α7nAChR 从脱敏中恢复。此外，当用α7nAChR 选择性拮抗剂甲基-lycaconitine 完全阻断烟碱诱发的电流时，RO5126946 的作用消失。RO5126946 增强了α7nAChR 突触传递并正向调节 GABA 能反应。RO5126946 对人α4β2nAChR 和 5-羟色胺 3 受体等无作用表明其对α7nAChR 的选择性。在体内，RO5126946 可口服生物利用且可穿透脑，并改善大鼠东莨菪碱诱导的恐惧条件反射缺陷模型中的联想学习。此外，为了解药物相互作用对行为的潜在影响，在给予尼古丁的情况下研究了 RO5126946 的促认知作用。当两种化合物以亚阈值剂量给药时，RO5126946 增强了尼古丁对恐惧记忆的作用，而当两种化合物以有效剂量给药时，RO5126946 并未干扰观察到的促认知作用。总的来说，RO5126946 是一种具有认知增强特性的新型α7nAChR PAM。
