%0 Journal Article
%T Synthesis and Biological Evaluation of New CRH Analogues
%A Spyridon Papazacharias
%A Vassiliki Magafa
%A Nicole Bernad
%A George Pairas
%A Georgios A. Spyroulias
%A Jean Martinez
%A Paul Cordopatis
%J Bioinorganic Chemistry and Applications
%D 2010
%I Hindawi Publishing Corporation
%R 10.1155/2010/252348
%X A series of 7 new human/rat Corticotropin Releasing Hormone (h/r-CRH) analogues were synthesized. The induced alterations include substitution of Phe at position 12 with D-Phe, Leu at positions 14 and 15 with Aib and Met at positions 21 and 38 with Cys(Et) and Cys(Pr). The analogues were tested regarding their binding affinity to the CRH-1 receptor and their activity which is represented by means of percentage of maximum response in comparison to the native molecule. The results indicated that the introduction of Aib, or Cys derivatives although altering the secondary structure of the molecule, did not hinder receptor recognition and binding. 1. Introduction Ever since its identification by Vale et al. [1], Corticotropin Releasing Hormone (CRH) has proven to be a major neuromodulator responsible not only for the secretion of ACTH by the anterior pituitary gland but also for the regulation of the endocrine, autonomic, immunological and behavioral responses to stress [2¨C4]. Furthermore, this 41-amino acid neuropeptide displays a plethora of additional roles in either physiological homeostasis or pathogenic manifestations varying from the well-established implication on neuropsychiatric disorders [5, 6] to the yet to be clarified actions on various forms of cardiovascular diseases [7] obesity [8] or gut motility [9], among others. A series of studies demonstrating the extent and perplexity of the roles and implications of CRH led to the identification of other peptides appearing to possess a similar role [10¨C13]. Both the isolation and characterization of the CRH family receptors has been achieved revealing two receptor subtypes, one of them appearing as three splice variants (CRH-R1, CRH-R2¦Á, CRH-R2¦Â, and CRH-R2¦Ã). A binding protein (CRH-BP) was also described [14¨C18].The most-studied receptor types are CRH-R1, CRH-R2¦Á, and CRH-R2¦Â not only due to their vast distribution but also for their implication in physiological functions or disorders of great importance. CRH-R1 is broadly distributed in the brain and the pituitary gland but also appears in a number of peripheral tissues [19]. It possesses a critical role in mediating the hypophysiotropic action of CRH [20] but furthermore is involved in anxiogenic behaviours, depression and anxiety [21], anorexia and bulimia, drug seeking and withdrawal, and seizure [22, 23]. CRH-R2¦Á is mainly a brain receptor whereas CRH-R2¦Â is largely expressed in the periphery. The role of CRH-R2 is more diverse since it extends from ¡°stress-coping¡± responses (anxiolysis, hypotension) to gastric emptying, regulation of energy
%U http://www.hindawi.com/journals/bca/2010/252348/