Further optimization of the VU0486321 series of highly selective and CNS-penetrant mGlu₁ PAMs identified unique ‘molecular switches’ on the central aromatic ring that engendered positive cooperativity with multiple mGlu subtypes across the receptor family, resulting in compounds with comparable activity at Group I (mGlu_1/5) and Group III (mGlu_4/6/7/8) mGlu receptors, receptors. These exciting data suggests this PAM chemotype appears to bind to multiple mGlu receptors, and that subtype selectivity is dictated by the degree of cooperativity, not a subtype selective, unique allosteric binding site. Moreover, there is interesting therapeutic potential for mGlu_1/4/7/8 PAMs, as well as the first report of a GPCR allosteric ‘privileged structure’.

VU0486321 系列高选择性和 CNS 渗透性 mGlu ₁ PAM 的进一步优化在中央芳香环上鉴定了独特的“分子开关”，该开关与受体家族中的多个 mGlu 亚型产生正协同作用，从而产生在 I 组具有可比活性的化合物（ mGlu _1/5 ) 和组 III (mGlu _4/6/7/8 ) mGlu 受体，受体。这些令人兴奋的数据表明，这种 PAM 化学型似乎与多个 mGlu 受体结合，并且亚型选择性取决于协同程度，而不是选择性亚型、独特的变构结合位点。此外，mGlu _1/4/7/8具有有趣的治疗潜力 PAM，以及 GPCR 变构“特权结构”的第一份报告。