Allosteric modulators of ion channels typically alter the transitions rates between conformational states without changing the properties of the open pore. Here we describe a new class of positive allosteric modulators of N-methyl d-aspartate receptors (NMDARs) that mediate a calcium-permeable component of glutamatergic synaptic transmission and play essential roles in learning, memory and cognition, as well as neurological disease. EU1622-14 increases agonist potency and channel-open probability, slows receptor deactivation and decreases both single-channel conductance and calcium permeability. The unique functional selectivity of this chemical probe reveals a mechanism for enhancing NMDAR function while limiting excess calcium influx, and shows that allosteric modulators can act as biased modulators of ion-channel permeation.

离子通道的变构调节剂通常会在不改变开孔特性的情况下改变构象状态之间的转换速率。在这里，我们描述了一类新的N -甲基d正变构调节剂- 天冬氨酸受体 (NMDARs)，介导谷氨酸能突触传递的钙渗透成分，在学习、记忆和认知以及神经系统疾病中发挥重要作用。EU1622-14 增加激动剂效力和通道打开概率，减缓受体失活并降低单通道电导和钙渗透性。这种化学探针独特的功能选择性揭示了一种增强 NMDAR 功能同时限制过量钙内流的机制，并表明变构调节剂可以作为离子通道渗透的偏向调节剂。