title: TRH mimetics: differentiation of antiamnesic potency from antidepressant effect.
abstract: For the purpose of rational modification of the TRH molecule, we were pursuing an approach that consists of two steps: (1) 'obligatory' replacement of histidine with glutamine in TRH and (2) the application of conformational constraints for putative bioactive conformation I stabilized by an intramolecular hydrogen bond between C-terminal carboxamide proton and alpha-carbonyl of histidyl (glutaminyl), and conformation II formed by an intramolecular hydrogen bond between alpha-carbonyl of pyroglutamyl and prolinamide proton. Significant antiamnesic potency was discovered in the passive avoidance test (ECS and Scopolamine induced amnesia) for conformation II mimic (8S,10aS)-8-carbamoyl-1,2,3,6,7,8,9,10a- octahydro-5H,10H-pyrrolo[1,2-a][1,4]diazocin-5,10-dione (2) at doses of 0.1 and 1.0 mg/kg. EEG analysis indicates a mild activating effect of compound 2 on EEG, which is similar to that of piracetam and differs from hard amphetamine activation. Conformation I mimic 3-(2-carbamoylethyl)-2,3,6,7,8,8a-hexahydro-1H,4H-pyrrolo[1,2-a] pyrazin-1,4-dione (1) exhibited an antidepressant effect at a dose of 1 mg/kg. The transition from two putative quasi-cyclic bioactive conformations of TRH and its obligatory similar analogue [Gln2]-TRH to their cyclic mimics led to differentiation of antiamnesic and antidepressant activity of TRH.
authors.affiliation: Physico-Chemical Institute, National Academy of Sciences, Odessa, Ukraine.
authors.forename: A A
authors.initials: AA
authors.lastname: Mazurov
authors.forename: S A
authors.initials: SA
authors.lastname: Andronati
authors.forename: T I
authors.initials: TI
authors.lastname: Korotenko
authors.forename: N I
authors.initials: NI
authors.lastname: Sokolenko
authors.forename: A I
authors.initials: AI
authors.lastname: Dyadenko
authors.forename: Y E
authors.initials: YE
authors.lastname: Shapiro
authors.lastname: Gorbatyuk VYa
authors.forename: T A
authors.initials: TA
authors.lastname: Voronina
mesh_terms: D000595:Amino Acid Sequence; D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D001392:Azocines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D004569:Electroencephalography / Q000187:drug effects; D000860:Hypoxia / Q000517:prevention & control; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011719:Pyrazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology*
chemical_list: C110102:3-(2-carbamoylethyl)-2,3,6,7,8,8a-hexahydro-1H,4H-pyrrolo(1,2-a)pyrazin-1,4-dione; C110101:8-carbamoyl-1,2,3,6,7,8,9,10a-octahydro-5H,10H-pyrrolo(1,2-a)(1,4)diazocin-5,10-dione; D000928:Antidepressive Agents; D001392:Azocines; D011719:Pyrazines; D011758:Pyrroles; D013973:Thyrotropin-Releasing Hormone