title: Synthesis, receptor binding, and CNS pharmacological studies of new thyrotropin-releasing hormone (TRH) analogues.
abstract: 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 in vitro, and in vivo 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 21 a (R=CH3) exhibited binding affinities (Ki values) of 0.17 μM for TRH-R1 and 0.016 μM 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 21 a, the most selective agonist, activated TRH-R2 with a potency (EC50 value) of 0.0021 μM, but activated TRH-R1 at EC50=0.05 μM, and exhibited 24-fold selectivity for TRH-R2 over TRH-R1. The newly synthesized TRH analogues were also evaluated in vivo to assess their potencies in antagonism of barbiturate-induced sleeping time, and several analogues displayed potent analeptic activity. Specifically, analogues 21 a,b and 22 a,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 10 μmol kg(-1). The results of this study provide evidence that TRH analogues that show selectivity for TRH-R2 over TRH-R1 possess potent CNS activity.
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India.
authors.forename: Vikramdeep
authors.initials: V
authors.lastname: Monga
authors.forename: Chhuttan L
authors.initials: CL
authors.lastname: Meena
authors.forename: Satyendra
authors.initials: S
authors.lastname: Rajput
authors.forename: Chandrashekhar
authors.initials: C
authors.lastname: Pawar
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Sharma
authors.forename: Xinping
authors.initials: X
authors.lastname: Lu
authors.forename: Marvin C
authors.initials: MC
authors.lastname: Gershengorn
authors.forename: Rahul
authors.initials: R
authors.lastname: Jain
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D004195:Disease Models, Animal; D051379:Mice; D011485:Protein Binding; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000819:agonists* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D018025:Receptors, Thyrotropin-Releasing Hormone; D013973:Thyrotropin-Releasing Hormone