Synthesis and biological characterization of [3.1.0], [3.2.0], [3.3.0], and [3.4.0] bicyclic pyrrolidine analogs as D4 and sigma 1 receptor dual modulators

Dopamine D4 (D4R) and sigma-1 (σ1R) receptors represent attractive targets for the treatment of neurological disorders, including L-DOPA–induced dyskinesias associated with Parkinson’s disease. Guided by prior work on D4R antagonists and σ1R modulators, we designed and synthesized a series of sp³-rich bicyclic pyrrolidine scaffolds ([3.1.0]–[3.4.0]) using a modular [3+2] cycloaddition strategy that enabled rapid exploration of structural diversity. In vitro profiling revealed pronounced structure–activity relationships driven by ring size and southern substituents, with the compact [3.1.0] and [3.2.0] scaffolds exhibiting optimal physicochemical properties and potent dual activity, including D4R Ki values of 1–5 nM and σ1R Ki values 3). Lead compounds 9b and 12b demonstrated favorable exposure and half-life in rat cassette studies, with discrete mouse pharmacokinetics confirming sustained brain concentrations well above D4R Ki values. Collectively, these findings establish bicyclic pyrrolidines as a versatile chemotype for dual D4R/σ1R modulation and identify 9b and 12b as promising in vivo tool compounds and leads for further optimization toward L-DOPA–induced dyskinesia.