Scalabrino Gaia A, Hogan Nicola, O'Boyle Kathy M, Slator Gillian R, Gregg Daniel J, Fitchett Christopher M, Draper Sylvia M, Bennett Geoffrey W, Hinkle Patricia M, Bauer Karl, Williams Carvell H, Tipton Keith F, Kelly Julie A
School of Biochemistry and Immunology and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
Neuropharmacology. 2007 Jun;52(7):1472-81. doi: 10.1016/j.neuropharm.2007.02.003. Epub 2007 Feb 28.
Thyrotropin-releasing hormone (TRH) displays multiple CNS-mediated actions that have long been recognized to have therapeutic potential in treating a wide range of neurological disorders. Investigations of CNS functions and clinical use of TRH are hindered, however, due to its rapid degradation by TRH-degrading ectoenzyme (TRH-DE). We now report the discovery of a set of first-in-class compounds that display unique ability to both potently inhibit TRH-DE and bind to central TRH receptors with unparalleled affinity. This dual pharmacological activity within one molecular entity was found through selective manipulation of peptide stereochemistry. Notably, the lead compound of this set, L-pyroglutamyl-L-asparaginyl-L-prolyl-D-tyrosyl-D-tryptophan amide (Glp-Asn-Pro-D-Tyr-D-TrpNH(2)), is effective in vivo at producing and potentiating central actions of TRH without evoking release of thyroid-stimulating hormone (TSH). Specifically, this peptide displayed high plasma stability and combined potent inhibition of TRH-DE (K(i) 151 nM) with high affinity binding to central TRH receptors (K(i) 6.8 nM). Moreover, intraperitoneal injection of this peptide mimicked and augmented the effects of TRH on behavioural activity in rat. Analogous to TRH, it also antagonized pentobarbital-induced narcosis when administered intravenously. This discovery provides new opportunities for probing the role of TRH actions in the CNS and a basis for development of novel TRH-based neurotherapeutics.
促甲状腺激素释放激素（TRH）具有多种由中枢神经系统介导的作用，长期以来人们一直认为这些作用在治疗多种神经系统疾病方面具有治疗潜力。然而，由于TRH会被TRH降解外切酶（TRH-DE）迅速降解，中枢神经系统功能的研究以及TRH的临床应用受到了阻碍。我们现在报告发现了一类首创的化合物，它们具有独特的能力，既能有效抑制TRH-DE，又能以无与伦比的亲和力与中枢TRH受体结合。通过对肽立体化学的选择性操纵，在一个分子实体中发现了这种双重药理活性。值得注意的是，该系列的先导化合物L-焦谷氨酰-L-天冬酰胺基-L-脯氨酰-D-酪氨酰-D-色氨酸酰胺（Glp-Asn-Pro-D-Tyr-D-TrpNH₂）在体内能有效产生并增强TRH的中枢作用，而不会引起促甲状腺激素（TSH）的释放。具体而言，这种肽具有高血浆稳定性，对TRH-DE具有强效抑制作用（抑制常数K(i)为151 nM），同时与中枢TRH受体具有高亲和力结合（K(i)为6.8 nM）。此外，腹腔注射这种肽可模拟并增强TRH对大鼠行为活动的影响。与TRH类似，静脉注射时它也能拮抗戊巴比妥诱导的麻醉。这一发现为探究TRH作用在中枢神经系统中的作用提供了新机会，并为开发新型基于TRH的神经治疗药物奠定了基础。
