Central nervous system effects of thyrotropin-releasing hormone and its analogues: opportunities and perspectives for drug discovery and development.
Besides its well-known endocrine role in the thyroid system, thyrotropin-releasing hormone (L-pyroglutamyl-L-histidyl-L-prolinamide) has been long recognized as a modulatory neuropeptide. After a brief overview of the extrahypothalamic and receptor distribution, and of the neurophysiological, neuropharmacological and neurochemical effects of this tripeptide, this review discusses efforts devoted to enhance therapeutically beneficial central nervous system effects via structural modifications of the endogenous peptide. An enormous array of maladies affecting the brain and the spinal cord has been a potential target for therapeutic interventions involving agents derived from thyrotropin-releasing hormone as a molecular lead. Successful development of several centrally active analogues and recent accounts of efforts aimed at improving metabolic stability, selectivity and bioavailability are highlighted.
Prokai
Laszlo
L
Center for Drug Discovery, College of Pharmacy, and the McKnight Brain Institute, University of Florida Health Science Center, Gainesville, FL 32610-0497, USA.
D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000378:metabolism; D013678:Technology, Pharmaceutical / Q000379:methods* / Q000639:trends; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D018025:Receptors, Thyrotropin-Releasing Hormone; D013973:Thyrotropin-Releasing Hormone