GTS 21 dihydrochloride

GTS 21 dihydrochloride is a novel agonist of nicotinic acetylcholine receptors (nAChRs) [1].
nAChRs are neuron receptor proteins that activated by the binding of the neurotransmitter acetylcholine (ACh).  
In RAW 264.7 cells (a macrophage like cell line) exposed to hyperoxia (≥99% O2), GTS-21 significantly increased phagocytic activity of macrophages in a dose-dependent way and reduced hyperoxia-induced hyperacetylation of HMGB1. Also, GTS-21 inhibited the cytoplasmic translocation and release of HMGB1 from these macrophages [1]. GTS-21 bound to human α4β2 nAChR (Ki value of 20 nM) 100-fold more potently than to human α7 nAChR, and was 2- and 18-fold less potent than (2)-nicotine at human α7 and α4β2 nAChR, respectively [2].    
In mice that were exposed to hyperoxia (≥99% O2) and subsequently challenged with PA, intraperitoneal injection of GTS-21 (4 mg/kg) significantly increased bacterial clearance, decreased accumulation of airway HMGB1 and decreased acute lung injury [1]. GTS-21 stimulated dopamine release from rat striatal slices with an EC50 of 10uM. In the delayed matching-to-sample task, GTS-21 (32–130 nmol/kg) improved learning performance of monkeys [2].
References:
[1]. Sitapara RA, Antoine DJ, Sharma L, et al. The α7 nicotinic acetylcholine receptor agonist GTS-21 improves bacterial clearance in mice by restoring hyperoxia-compromised macrophage function. Mol Med, 2014, 20: 238-247.
[2]. Briggs CA, Anderson DJ, Brioni JD, et al. Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo. Pharmacol Biochem Behav, 1997, 57(1-2): 231-241.

Hydroxy metabolites of the Alzheimer's drug candidate 3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride (GTS-21): their molecular properties, interactions with brain nicotinic receptors, and brain penetration.[Pubmed:14722237]

Mol Pharmacol. 2004 Jan;65(1):56-67.

3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride (DMXBA; GTS-21), an Alzheimer's drug candidate, selectively stimulates alpha7 nicotinic acetylcholine receptors. It rapidly enters the brain after oral administration and enhances cognitive behavior. Less than 1% of orally administered DMXBA is recovered in the urine. We report the identification and characterization of the major phase I metabolites of this drug candidate. Three hydroxy metabolites were generated in vitro by hepatic microsomal O-dealkylation of the two methoxy substituents on the benzylidene ring. They were also found in plasma of rats after oral administration, but at significantly lower concentrations relative to the parent compound. The metabolites displayed similar binding affinities and partial agonist potencies at rat brain alpha7 receptors. However, each displayed a higher efficacy than DMXBA for stimulating rat and human alpha7 receptors. Like DMXBA, the metabolites were weak antagonists at alpha4beta2 receptors. The predicted conformations of the metabolites were nearly identical with that of DMXBA. Ionization of the tetrahydropyridyl nitrogen was essential for high-affinity binding of DMXBA to the alpha7 receptor. The hydroxy metabolites were much more polar than DMXBA, derived from their experimentally estimated octanol/water partition coefficients, and they entered the brain much less readily than DMXBA. Their contributions to the behavioral effects of orally administered DMXBA, if any, would probably be very small during short-term administration. Benzylidene anabaseines pharmacologically similar to the hydroxy metabolites, but which enter the brain more readily, may provide greater stimulation of alpha7 receptors in the whole organism.

Nicotinic mechanisms in the treatment of psychotic disorders: a focus on the alpha7 nicotinic receptor.[Pubmed:23027417]

Handb Exp Pharmacol. 2012;(213):211-32.

Nicotine is heavily abused by persons with schizophrenia. Nicotine better enables people with schizophrenia to filter out extraneous auditory stimuli. Nicotine also improves prepulse inhibition when compared to placebo. Nicotine similarly increases the amplitude of patients' duration mismatch negativity. The 15q13-14 region of the genome coding for the alpha7 nicotinic receptor is linked to schizophrenia. Multiple single nucleotide polymorphisms have been identified in this 15q13-14 gene promoter region that are more frequently present in people with schizophrenia than in normal controls. Abnormalities in expression and regulation of central nicotinic cholinoceptors with decreased alpha7 binding in multiple brain regions are also present. Nicotine enhances cognition in schizophrenia. Alternative agents that activate the nicotinic receptor have been tested including 3-[2,4-dimethoxybenzylidene]anabaseine (DMXB-A). This compound improved attention, working memory, and negative symptoms in an add-on study in nonsmoking patients with schizophrenia. There are multiple other nicotinic agents, including positive allosteric modulators, in the preclinical stages of development. Finally, the effects of varenicline and clozapine and their relation to smoking cessation are discussed.

Continuous administration of a selective alpha7 nicotinic partial agonist, DMXBA, improves sensory inhibition without causing tachyphylaxis or receptor upregulation in DBA/2 mice.[Pubmed:20599427]

Brain Res. 2010 Sep 17;1352:140-6.

Stimulation of nicotinic receptors, specifically the alpha7 subtype, improves sensory inhibition and cognitive function in receptor deficient humans and rodents. However, stimulation with a full agonist, such as nicotine, produces rapid tachyphylaxis of the P20N40-measured sensory inhibition process. 3-(2,4-dimethoxybenzylidine) anabaseine (DMXBA, also GTS-21) selectively activates the alpha7 nicotinic receptor, and in acute administration studies, has been shown to improve deficient sensory inhibition in both humans and rodents with repeated dosing. Unlike nicotine, this partial agonist acted without inducing tachyphylaxis. Here, we assessed the ability of DMXBA to improve sensory inhibition in DBA/2 mice after 7 days of continuous administration via a subcutaneously implanted osmotic minipump. When assessed on day 8, mice receiving saline showed the characteristic deficient sensory inhibition seen with untreated DBA/2 mice. The 25- and 50-mg/ml infusion concentrations of DMXBA, but not the 100-mg/ml, produced significantly improved sensory inhibition in the mice, exclusively through a decrease in test amplitude. No concentration significantly upregulated hippocampal alpha7 receptor levels. DMXBA levels in the brain were higher than plasma at 2 of the 3 concentrations infused. These data suggest that continuous exposure to DMXBA does not significantly affect the underlying responsiveness of the sensory inhibition pathway to this partial agonist, nor cause receptor upregulation, at these relatively low brain concentrations. The ability of DMXBA to maintain its effectiveness during constant administration conditions may be due to an ability to activate alpha7 receptors at low concentrations, and consequently low fractional occupancy of the five possible binding sites on this homomeric receptor.

GTS-21 dihydrochloride is a selective α7 nicotinic acetylcholine receptor agonist, has recently been established as a promising treatment for inflammation.

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