Discovery of a dual action first-in-class peptide that mimics and enhances CNS-mediated actions of thyrotropin-releasing hormone

摘要: Thyrotropin-releasing hormone (TRH) displays multiple CNS-mediated actions that have long been recognized to therapeutic potential in treating a wide range of neurological disorders. Investigations CNS functions and clinical use TRH are hindered, however, due its rapid degradation by TRH-degrading ectoenzyme (TRH-DE). We now report the discovery set first-in-class compounds display unique ability both potently inhibit TRH-DE bind central receptors with unparalleled affinity. This dual pharmacological activity within one molecular entity was found through selective manipulation peptide stereochemistry. Notably, lead compound this set, L-pyroglutamyl-L-asparaginyl-L-prolyl-D-tyrosyl-D-tryptophan amide (Glp-Asn-Pro-D-Tyr-D-TrpNH(2)), is effective vivo at producing potentiating without evoking release thyroid-stimulating (TSH). Specifically, displayed high plasma stability combined potent inhibition (K(i) 151 nM) affinity binding 6.8 nM). Moreover, intraperitoneal injection mimicked augmented effects on behavioural rat. Analogous TRH, it also antagonized pentobarbital-induced narcosis when administered intravenously. provides new opportunities for probing role basis development novel TRH-based neurotherapeutics.