Thyrotropin-releasing hormone (TRH) analogues that exhibit selectivity to TRH receptor subtype 2

Thyrotropin-releasing hormone (TRH) analogues in which the C-2 position of the imidazole ring of the centrally placed histidine residue is substituted with various alkyl groups were synthesized and studied as agonists for TRH receptor subtype 1 (TRH-R1) and subtype 2 (TRHR2). Several analogues were found to be selective agonists for TRH-R2 exhibiting no activation of TRH-R1. For example, analogue 4 (R = c-C3H5) was found to activate TRH-R2 with a potency (EC50) of 0.41 mu M but did not activate TRH-R1 (potency > 100 mu M). This study describes the first discovery of TRH-R2-specific agonists and provides impetus to design predominately CNS-effective TRH peptides.