Modifications at C(5) of 2‑(2-Pyrrolidinyl)-Substituted 1,4-Benzodioxane Elicit Potent α4β2 Nicotinic Acetylcholine Receptor Partial Agonism with High Selectivity over the α3β4 Subtype

A series of diastereomeric
2-(2-pyrrolidinyl)-1,4-benzodioxanes
bearing a small, hydrogen-bonding substituent at the 7-, 6-, or 5-position
of benzodioxane have been studied for α4β2 and α3β4
nicotinic acetylcholine receptor affinity and activity. Analogous
to C(5)H replacement with N and to a much greater extent than decoration
at C(7), substitution at benzodioxane C(5) confers very high α4β2/α3β4
selectivity to the α4β2 partial agonism. Docking into
the two receptor structures recently determined by cryo-electron microscopy
and site-directed mutagenesis at the minus β2 side converge
in indicating that the limited accommodation capacity of the β2
pocket, compared to that of the β4 pocket, makes substitution
at C(5) rather than at more projecting C(7) position determinant for
this pursued subtype selectivity.

本研究针对一系列在苯并二氧六环（benzodioxane）的7位、6位或5位带有小型氢键结合取代基的非对映异构2-(2-吡咯烷基)-1,4-苯并二氧六环（2-(2-pyrrolidinyl)-1,4-benzodioxanes），系统评价了其针对α4β2与α3β4烟碱型乙酰胆碱受体（nicotinic acetylcholine receptor）的亲和力与活性。相较于C(7)位的官能团修饰，在苯并二氧六环C(5)位将C-H替换为氮原子的修饰效果更为显著，该位点取代可使α4β2部分激动活性获得极高的α4β2/α3β4亚型选择性。通过对接至近期通过冷冻电子显微镜（cryo-electron microscopy）解析的两种受体结构，并结合针对β2亚基负向结合界面的定点诱变实验结果，二者共同表明：相较于β4亚基结合口袋，β2亚基结合口袋的配体容纳能力更为有限，这使得苯并二氧六环C(5)位的取代（而非空间位阻更高、更突出的C(7)位取代）成为实现该目标亚型选择性的关键决定因素。