Novel 5α-reductase inhibitors unlinked to depression-like phenotypes in rat model of BPH

Finasteride clinically approved for the treatment of benign prostatic hyperplasia exerts its therapeutic effect by inhibiting type II 5α-reductase, thereby reducing dihydrotestosterone levels, leading to prostate shrinkage and symptomatic relief. However, finasteride also influences the levels of neurosteroids (allopregnanolone) and has been linked to depression-like behavior and impaired neurogenesis. Preclinical and clinical studies have shown that finasteride can robustly induce depressive behavior and can inhibit hippocampal neurogenesis in mice attributed to altered neurosteroids levels. Hence discovery and development of 5α-reductase inhibitors that are effective and devoid of depressionlike effect is essential. The aim of the present study is to assess the safety profile of newly synthesised steroidal 5α-reductase inhibitors. Six compounds from two series were synthesized and screened. Based on in silico docking against human 5α-reductase type II and reduction of serum DHT levels, ND-1 and ND-5 were identified as lead candidates. Both showed strong binding affinities (ND-1: -10.2 kcal/mol; ND-5: -9.8 kcal/mol) comparable to finasteride (-10.5 kcal/mol) and significantly reduced serum DHT in vivo. ND-1 and ND-5 were further evaluated in a testosterone-induced BPH rat model and assessed for depression-like effects following chronic treatment using locomotor activity, sucrose splash, and forced swim tests, along with serum allopregnanolone estimation. In the BPH model, both compounds markedly decreased prostate weight, seminal vesicle weight, demonstrating efficacy comparable to finasteride. Importantly, unlike finasteride, they did not induce depression-like behaviour and preserved serum allopregnanolone levels, highlighting their potential as safer alternatives. However, further studies are required to understand the underlying molecular mechanisms.