Modifications of the pyroglutamic acid and histidine residues in thyrotropin-releasing hormone (TRH) yield analogs with selectivity for TRH receptor type 2 over type 1

Thyrotropin -releasing hormone (TRH) analogs in which the N-l(tau) or the C-2 position of the imidazole ring of the histidine residue is substituted with various alkyl groups and the L-pyroglutamic acid (pGlu) is replaced with the L-pyro-2-aminoadipic acid (pAad) or (R)- and (S)-3-oxocyclopentane-1-carboxylic acid (Ocp) were synthesized and studied as agonists for TRH receptor subtype 1 (TRH-R1) and subtype 2 (TRH-R2). We observed that several analogs were selective agonists of TRH-R2 showing relatively less or no activation of TRH-R1. For example, the most selective agonist of the series 13, in which pGlu is replaced with the pAad and histidine residue is substituted at the N-1 position with an isopropyl group, was found to activate TRH-R2 with a potency (EC50 = 1.9 mu M) but did not activate TRH-R1 (potency > 100 mu M); that is, exhibited > 51-fold greater selectivity for TRH-R2 versus TRH-R1. Analog 8, in which pGlu is replaced with pAad and histidine is substituted at the N-1(tau) position with a methyl group, exhibited a binding affinity (K-i = 0.0032 mu M) to TRH-R1 that is similar to that of [N tau(1)-Me-His]-TRH and displayed potent activation of TRH-R1 and TRH-R2 (EC50 = 0.0049 and 0.0024 mu M, respectively). None of the analogs in which pGlu is replaced with the bioisosteric (R)- and (S)-(Ocp) and the imidazole ring is substituted at the N-1(tau) or C-2 position were found to bind or activate either TRH-R1 or TRH-R2 at the highest test dose of 100 mu M. (c) 2006 Elsevier Ltd. All rights reserved.