Synthesis and neurotrophic activity of nonimmunosuppressant cyclosporin A derivatives

• Published in: Bioorganic & medicinal chemistry letters 2004-09, Vol.14 (17), p.4549-4551
• Main Authors: Wei, Ling, Steiner, Joseph P, Hamilton, Gregory S, Wu, Yong-Qian
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Chickens; Cyclosporine - chemical synthesis; Cyclosporine - pharmacology; Dose-Response Relationship, Drug; Ganglia, Spinal - cytology; Ganglia, Spinal - drug effects; Immunosuppressive Agents - chemistry; Immunosuppressive Agents - pharmacology; Medical sciences; Miscellaneous; Nerve Growth Factors - chemical synthesis; Nerve Growth Factors - genetics; Nerve Growth Factors - pharmacology; Pharmacology. Drug treatments
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.06.028

In order to exploit cyclophilin as a potential target for neurological drug design, we demonstrate in this presentation that several nonimmunosuppressant analogues of cyclosporin A, modified at the various positions in the `effector' domain, are equipotent nerve growth agents compared to cyclosporin A. Our results suggest that neurotrophic activity of cyclosporin A and its derivatives resides in the binding domain, and binding to cyclophilin and/or inhibiting rotamase activity may be a necessity for neurotrophic effects of cyclophilin ligands. In order to exploit cyclophilin as a potential target for neurological drug design, we demonstrate in this presentation that several nonimmunosuppressant analogues of cyclosporin A, modified at the various positions in the `effector' domain, are equipotent nerve growth agents compared to cyclosporin A. Our results suggest that neurotrophic activity of cyclosporin A and its derivatives resides in the binding domain, and binding to cyclophilin and/or inhibiting rotamase activity may be a necessity for neurotrophic effects of cyclophilin ligands.