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Synthesis and bioactivity of psilocybin analogues containing a stable carbon–phosphorus bond

Summary

Researchers created new chemical versions of psilocybin (the active compound in magic mushrooms) that cannot be broken down by the body’s natural enzymes in the same way. They tested these new compounds to see if they could help with depression and anxiety by targeting specific brain receptors. The best compound worked well on the intended brain receptors but importantly showed less activity on a heart-related receptor, potentially making it safer than natural psilocybin.

Background

Psilocybin and related psychedelic compounds show promise for treating major depressive disorder and treatment-resistant depression, but their hallucinogenic nature limits clinical use. Current antidepressants have limited efficacy and significant side effects. Recent research has identified selective binding modes of psilocin that produce therapeutic effects without hallucinations.

Objective

To synthesize psilocybin analogues containing non-hydrolysable carbon-phosphorus bonds and evaluate their biological activity and selectivity toward 5-HT2AR, 5-HT2BR, and TNAP receptors. The goal was to determine if phosphonate analogues could inhibit alkaline phosphatase metabolism while maintaining or improving receptor selectivity.

Results

All synthesized compounds showed no affinity for TNAP, disproving the inhibition hypothesis. However, clear structure-activity relationships emerged for serotonergic receptors, with phosphonate esters of N,N-dimethyltryptamine (compound 9) showing the highest potency. Compound 9 demonstrated higher binding affinity for 5-HT2AR than psilocybin and significantly lower selectivity for 5-HT2BR compared to psilocin, which is favorable for reducing valvular heart disease risk.

Conclusion

The phosphonate analogues successfully demonstrate receptor binding activity with promising selectivity profiles. Compound 9 exhibits reduced 5-HT2BR selectivity compared to psilocin, potentially minimizing cardiotoxicity concerns. These findings provide structural insights for designing selective psilocybin analogues with improved therapeutic profiles for psychiatric disorders.
  • Published in:RSC Medicinal Chemistry,
  • Study Type:Chemical Synthesis and In Vitro Pharmacology Study,
  • Source: 10.1039/d4md00043a, PMID: 38516602
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