Identification and optimisation of a series of tetrahydrobenzotriazoles as metabotropic glutamate receptor 5-selective positive allosteric modulators that improve performance in a preclinical model of cognition.

Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable compound for progression to in vivo safety evaluation.

The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists.

A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit.

Preclinical investigations into the antipsychotic potential of the novel histamine H3 receptor antagonist GSK207040.

OBJECTIVES: To test the novel nonimidazole histamine H3 receptor antagonist 5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazapin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide (GSK207040) in a series of behavioral and neurochemical paradigms designed to evaluate its antipsychotic potential. MATERIALS AND METHODS: Acute orally administered GSK207040 was investigated for its capacity to reverse a 24-h-induced deficit in novel object recognition memory, deficits in prepulse inhibition (PPI) induced by isolation rearing, and hyperlocomotor activity induced by amphetamine. The acute neurochemical effects of GSK207040 were explored by analyzing rat anterior cingulate cortex microdialysates for levels of dopamine, noradrenaline, and acetylcholine and by c-fos immunohistochemistry. The potential for interaction with the antipsychotic dopamine D2 receptor antagonist haloperidol was explored behaviorally (spontaneous locomotor activity and catalepsy), biochemically (plasma prolactin), and via ex vivo receptor occupancy determinations. RESULTS: GSK207040 significantly enhanced object recognition memory (3 mg/kg) and attenuated isolation rearing-induced deficits in PPI (1.0 and 3.2 mg/kg) but did not reverse amphetamine-induced increases in locomotor activity. There was no evidence of an interaction of GSK207040 with haloperidol. GSK207040 (3.2 mg/kg) raised extracellular concentrations of dopamine, noradrenaline, and acetylcholine in the anterior cingulate cortex and c-fos expression in the core of the nucleus accumbens was increased at doses of 3.2 and 10.0 mg/kg. CONCLUSIONS: The behavioral and neurochemical profile of GSK207040 supports the potential of histamine H3 receptor antagonism to treat the cognitive and sensory gating deficits of schizophrenia. However, the failure of GSK207040 to reverse amphetamine-induced locomotor hyperactivity suggests that the therapeutic utility of histamine H(3) receptor antagonism versus positive symptoms is less likely, at least following acute administration.

Effect of the selective dopamine D3 receptor antagonist SB-277011-A on regional c-Fos-like expression in rat forebrain.

SB-277011-A is a dopamine D(3) receptor antagonist that exhibits over 100-fold selectivity over dopamine D(2) receptors and a broad spectrum of other receptor, ion channels, and enzymes. We employed c-Fos immunohistochemistry to characterise the functional neuroanatomical effects of acute administration of SB-277011-A and observed a time-dependent increase in the density of c-Fos-like positive nuclei in rat forebrain with maximal effects observed 2 h post-dose. The relative influence of the different brain regions on the overall effect of SB-277011-A was ranked by partial least squares discriminant analysis loadings plot which indicated that sites within the nucleus accumbens exerted the greatest influence on the separation of the vehicle and SB-277011-A treatment groups. At the 2 h time-point, c-Fos-like expression was shown to be significantly elevated (p<0.05) in the core and shell of the nucleus accumbens, at both rostral and caudal levels, and in the lateral septum. No significant changes were detected in the caudate nucleus (lateral or medial) or in the cingulate, infralimbic prefrontal, or somatosensory cortices. The capacity of SB-277011-A to trigger immediate early gene expression in these limbic regions of rat brain adds to a growing consensus of the potential utility of dopamine D(3) receptor antagonism in psychiatric disorders including schizophrenia and drug dependency.

Urotensin-II, a neuropeptide ligand for GPR14, induces c-fos in the rat brain.

The vasoactive peptide urotensin-II and its receptor, GPR14 (now known as UT receptor), are localised in the mammalian central nervous system. Accordingly, various centrally mediated effects of urotensin-II on behaviour, neuroendocrine hormones and neurochemistry have been described. To investigate neuroanatomical substrates for the central actions of urotensin-II, expression of the immediate early gene c-fos was examined following intracerebroventricular administration to rats. Urotensin-II increased Fos expression in the cingulate cortex and periaqueductal grey, suggesting important central roles for urotensin-II and its receptor.

Attenuation of amphetamine-induced activity by the non-selective muscarinic receptor agonist, xanomeline, is absent in muscarinic M4 receptor knockout mice and attenuated in muscarinic M1 receptor knockout mice.

The muscarinic acetylcholine receptor (mAChR) agonist, xanomeline, attenuates amphetamine-induced activity in WT mice. This effect is abolished in mice lacking the M(4) muscarinic acetylcholine receptor (M(4) mAChR KO) and partially attenuated in mice lacking M(1) muscarinic acetylcholine receptor (M(1) mAChR KO). Collectively, these data suggest that the efficacy exhibited by xanomeline in the mouse amphetamine-induced hyperactivity model, is mediated predominantly by M(4) muscarinic acetylcholine receptors, and that M(1) muscarinic acetylcholine receptors may play a more minor role. This supports the hypothesis that activation of M(4), and to a lesser extent M(1) muscarinic acetylcholine receptors, may represent a potential target for the treatment of psychosis seen in schizophrenia.