THIP hydrochloride

Enantiotropically related polymorphs of gaboxadol hydrochloride.[Pubmed:24192165]

Acta Crystallogr C. 2013 Nov;69(Pt 11):1234-7.

Gaboxadol hydrochloride, also known as THIP hydrochloride (systematic name: 3-hydroxy-4,5,6,7-tetrahydro-1,2-oxazolo[5,4-c]pyridin-6-ium chloride), C6H9N2O2(+).Cl(-), exists as two enantiotropically related polymorphs. Transformation between the polymorphs occurs in a single-crystal-to-single-crystal manner at 221 K, and the enthalpy of transformation from the high-temperature form to the low-temperature form is -0.7 kJ mol(-1). Single-crystal structures have been determined at 298 and 220 K. At 298 K, the structure is triclinic (space group P overline 1), with two formula units in the crystallographic asymmetric unit. At 220 K, the structure is monoclinic (space group I2/a), with one formula unit in the asymmetric unit. The structures contain identical hydrogen-bonded layers and the transformation between the polymorphs corresponds to a shift of adjacent layers relative to each other. The transformation is shown to be reversible by differential scanning calorimetry and variable-temperature powder X-ray diffraction.

The role of GABAergic system on the inhibitory effect of ghrelin on food intake in neonatal chicks.[Pubmed:22613635]

Neurosci Lett. 2012 Jun 27;520(1):82-6.

Ghrelin is a gut-brain peptide that has a stimulatory effect on food intake in mammals. In contrast, this peptide decreases food intake in neonatal chicks when injected intracerebroventricularly (ICV). In mammals, neuropeptide Y (NPY) mediates the orexigenic effect of ghrelin whereas in chicks it appears that corticotrophin releasing factor (CRF) is partially involved in the inhibitory effect of ghrelin on food intake. Gamma aminobutyric acid (GABA) has a stimulatory effect on food intake in mammals and birds. In this study we investigated whether the anorectic effect of ghrelin is mediated by the GABAergic system. In Experiment 1, 3h-fasted chicks were given an ICV injection of chicken ghrelin and picrotoxin, a GABA(A) receptors antagonist. Picrotoxin decreased food intake compared to the control chicks indicating a stimulatory effect of GABA(A) receptors on food intake. However, picrotoxin did not alter the inhibitory effect of ghrelin on food intake. In Experiment 2, THIP hydrochloride, a GABA(A) receptor agonist, was used in place of picrotoxin. THIP hydrochloride appeared to partially attenuate the decrease in food intake induced by ghrelin at 30 min postinjection. In Experiment 3, the effect of ICV injection of chicken ghrelin on gene expression of glutamate decarboxylase (GAD)(1) and GAD(2), GABA synthesis enzymes in the brain stem including hypothalamus, was investigated. The ICV injection of chicken ghrelin significantly reduced GAD(2) gene expression. These findings suggest that ghrelin may decrease food intake in neonatal chicks by reducing GABA synthesis and thereby GABA release within brain feeding centers.

Gaboxadol. Lundbeck/Merck.[Pubmed:15298075]

Curr Opin Investig Drugs. 2004 Jul;5(7):766-73.

H Lundbeck A/S, in collaboration with Merck & Co Inc, is developing gaboxadol, a GABAA agonist, for the potential treatment of sleep disorders. The compound is currently undergoing phase III clinical trials.

GABAc receptors: relatively simple transmitter -gated ion channels?[Pubmed:8885697]

Trends Pharmacol Sci. 1996 Sep;17(9):319-23.

The inhibitory neurotransmitter, GABA, activates a variety of receptors in all areas of the CNS. Two major subtypes of GABA receptors are well known: (1) GABAA receptors are ligand-gated Cl- channels that consist of a heteromeric mixture of protein subunits forming a pentameric structure, and (2) GABAB receptors couple to Ca2+ and K+ channels via G proteins and second messengers. Here, Graham Johnston discusses evidence for a third major subclass of GABA receptors. GABAC receptors appear to be relatively simple ligand-gated Cl- channels with a distinctive pharmacology, in that they are not blocked by bicuculline and not modulated by barbiturates, benzodiazepines or neuroactive steroids. Compared with GABAA receptors, GABAC receptors are activated at lower concentrations of GABA and are less liable to desensitization. In addition, their channels open for a longer time. The pharmacology of these novel subtypes of GABA receptors may yield important therapeutic agents.

4,5,6,7-Tetrahydroisothiazolo[5,4-c]pyridin-3-ol and related analogues of THIP. Synthesis and biological activity.[Pubmed:6304315]

J Med Chem. 1983 Jun;26(6):895-900.

The thio analogues of the GABA (gamma-aminobutyric acid) agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), the GABA uptake inhibitor THPO (4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol), and the glycine antagonist THAZ (5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol) have been synthesized and tested biologically on single neurons in the cat spinal cord and in vitro by using synaptic membrane preparations obtained from rat brains. In contrast to THIP, thio-THIP (4,5,6,7-tetrahydroisothiazolo[5,4-c]pyridin-3-ol, 5) was only a weak GABA agonist. Thio-THPO (4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol, 10) was slightly weaker than THPO as an inhibitor of GABA uptake in vitro, and these two compounds were approximately equipotent in enhancing the inhibition of the firing of cat spinal neurons by GABA. Like THAZ and structurally related bicyclic isoxazole zwitterions, thio-THAZ (5,6,7,8-tetrahydro-4H-isothiazolo[4,5-d]azepin-3-ol, 15) was an antagonist at glycine receptors on cat spinal neurons. The I/U ratios, which reflect the ability of neutral amino acids to penetrate the blood-brain barrier (BBB), were calculated for 5 (I/U = 16), 10 (63), and 15 (200). These low I/U ratios, compared with the findings that THIP (I/U = 500 or 1500) and THPO (I/U = 2500) enter the brain after systemic administration, suggest that the thio analogues may penetrate the BBB very easily.

Gaboxadol hydrochloride (Lu 02-030 hydrochloride; THIP hydrochloride) is a potent agonist of the GABAA receptor and an antagonist of GABAC receptors (IC50=25 μM). Gaboxadol hydrochloride displays a partial agonist efficacy on subunit α1β2γ2 with an ED50 value of 143 µM, a full agonist efficacy at α5 subunit (ED50=28-129 µM) and a superagonist efficacy at α4β3δ (ED50=6 µM). Gaboxadol hydrochloride is a non-opioid analgesic and has hypnotic activities.

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