Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites

A group III metabotropic glutamate
(mGlu) receptor agonist (PCEP)
was identified by virtual HTS. This orthosteric ligand is composed
by an l-AP4-derived fragment that mimics glutamate and a
chain that binds into a neighboring pocket, offering possibilities
to improve affinity and selectivity. Herein we describe a series of
derivatives where the distal chain is replaced by an aromatic or heteroaromatic
group. Potent agonists were identified, including some with a mGlu4 subtype preference, e.g., 17m (LSP1-2111) and 16g (LSP4-2022). Molecular modeling suggests that aromatic
functional groups may bind at either one of the two chloride regulatory
sites. These agonists may thus be considered as particular bitopic/dualsteric
ligands. 17m was shown to reduce GABAergic synaptic transmission
at striatopallidal synapses. We now demonstrate its inhibitory effect
at glutamatergic parallel fiber–Purkinje cell synapses in the
cerebellar cortex. Although these ligands have physicochemical properties
that are markedly different from typical CNS drugs, they hold significant
therapeutic potential.

本研究通过虚拟高通量筛选（virtual HTS）鉴定出一种第三组代谢型谷氨酸（metabotropic glutamate, mGlu）受体激动剂PCEP。该正位配体由模拟谷氨酸的L-AP4衍生片段与可结合邻近结合口袋的链段构成，为提升配体的亲和力与选择性提供了可行策略。本文报道了一系列将远端侧链替换为芳香族或杂芳族基团的衍生物，本研究从中筛选得到多款强效激动剂，其中部分化合物对mGlu4亚型具有偏好性，例如17m（LSP1-2111）与16g（LSP4-2022）。分子建模研究表明，芳香官能团可结合于两个氯离子调控位点中的任意一个，因此这类激动剂可被视为特殊的双位点/双结合位配体（bitopic/dualsteric ligands）。此前已有研究证实17m可降低纹状体苍白球突触的GABA能突触传递，本研究则进一步验证了其对小脑皮层内谷氨酸能平行纤维-浦肯野细胞突触的抑制作用。尽管此类配体的理化性质与典型中枢神经系统（CNS）药物存在显著差异，但它们具备可观的治疗应用潜力。