1287270-42-1Relevant articles and documents
Synthesis, Receptor Binding, and CNS Pharmacological Studies of New Thyrotropin-Releasing Hormone (TRH) Analogues
Monga, Vikramdeep,Meena, Chhuttan L.,Rajput, Satyendra,Pawar, Chandrashekhar,Sharma, Shyam S.,Lu, Xinping,Gershengorn, Marvin C.,Jain, Rahul
, p. 531 - 543 (2012/02/14)
As part of our search for selective and CNS-active thyrotropin-releasing hormone (TRH) analogues, we synthesized a set of 44 new analogues in which His and pGlu residues were modified or replaced. The analogues were evaluated as agonists at TRH-R1 and TRH-R2 in cells invitro, and invivo in mice for analeptic and anticonvulsant activities. Several analogues bound to TRH-R1 and TRH-R2 with good to moderate affinities, and are full agonists at both receptor subtypes. Specifically, analogue 21a (R=CH3) exhibited binding affinities (Ki values) of 0.17μM for TRH-R1 and 0.016μM for TRH-R2; it is 10-fold less potent than TRH in binding to TRH-R1 and equipotent with TRH in binding to TRH-R2. Compound 21a, the most selective agonist, activated TRH-R2 with a potency (EC50 value) of 0.0021μM, but activated TRH-R1 at EC50=0.05μM, and exhibited 24-fold selectivity for TRH-R2 over TRH-R1. The newly synthesized TRH analogues were also evaluated invivo to assess their potencies in antagonism of barbiturate-induced sleeping time, and several analogues displayed potent analeptic activity. Specifically, analogues 21a,b and 22a,b decreased sleeping time by nearly 50% more than TRH. These analogues also displayed potent anticonvulsant activity and provided significant protection against PTZ-induced seizures, but failed to provide any protection in MES-induced seizures at 10μmolkg-1. The results of this study provide evidence that TRH analogues that show selectivity for TRH-R2 over TRH-R1 possess potent CNS activity.
