Efficacy of vestipitant, a neurokinin-1 receptor antagonist, in primary insomnia.

Study Objectives: Investigate the hypnotic effects of repeated doses of neurokinin-1 receptor antagonist, vestipitant, in primary insomnia.

Design: Randomized, double-blind, placebo-controlled 28-day parallel-group study.

Setting: Eleven sleep centers in Germany.

Slow dissociation of partial agonists from the D₂ receptor is linked to reduced prolactin release.

In this study we investigated the correlation between affinity, efficacy, peripheral receptor occupancy, and kinetic properties of D₂ dopamine receptor ligands with time-course evaluations of prolactin release in rat blood. We profiled typical and atypical antipsychotic antagonists at D₂ receptors, the partial agonist aripiprazole, and four novel partial agonist compounds with different properties. Clozapine and quetiapine revealed lower prolactin release and fast dissociation kinetics, linking fast dissociation and prolactin-sparing properties.

The efficacy of sodium channel blockers to prevent phencyclidine-induced cognitive dysfunction in the rat: potential for novel treatments for schizophrenia.

Sodium channel inhibition is a well precedented mechanism used to treat epilepsy and other hyperexcitability disorders. The established sodium channel blocker and broad-spectrum anticonvulsant lamotrigine is also effective in the treatment of bipolar disorder and has been evaluated in patients with schizophrenia. Double-blind placebo-controlled clinical trials found that the drug has potential to reduce cognitive symptoms of the disorder.

Pyrrolo[1,2-a]pyrazine and pyrazolo[1,5-a]pyrazine: novel, potent, and selective series of Vasopressin 1b receptor antagonists.

Novel series of pyrrole-pyrazinone and pyrazole-pyrazinone have been identified as potent and selective Vasopressin(1b) receptor antagonists. Exploration of the substitution pattern around the core of these templates allowed generation of compounds with high inhibitory potency at the Vasopressin(1b) receptor, including examples that showed good selectivity with respect to Vasopressin(1a), Vasopressin(2), and Oxytocin receptor subtypes.

Microarray analysis of cultured rat hippocampal neurons treated with brain derived neurotrophic factor.

Brain derived neurotrophic factor (BDNF) has been shown to exert multiple actions on neurons. It plays a role in neuronal growth and maintenance and use-dependent plasticity, such as long-term potentiation and learning. This neurotrophin is believed to regulate neuronal plasticity by modifying neuronal excitability and morphology.

Recent advances in the discovery of selective and non-selective 5-HT(1D) receptor ligands.

This article highlights recent advances in the discovery of new agonists, antagonists and partial agonists of the 5-HT(1D) receptor. The field of 5-HT(1D) agonists continues to deliver a number of new potential therapeutic agents, although advances in this field are now more focussed on the clinical evaluation phase. The identification of novel compounds is greater for the 5-HT(1D) receptor antagonists, and whilst few truly selective ligands have been identified, a number of approaches are discussed towards defined mixed-pharmacology profiles.

The relationship between sodium channel inhibition and anticonvulsant activity in a model of generalised seizure in the rat.

The development of novel anticonvulsant drugs with improved efficacy for the treatment of epilepsy is hindered by a lack of information regarding the quantitative relationship between target mechanism and in vivo efficacy. In the present study we have examined the correlation between the potency of structurally diverse compounds at voltage-gated sodium channels in vitro and their efficacy in a rodent model of acute generalised seizures induced by electroshock. We observed a significant correlation between the estimated affinity (Ki) of the compounds for the inactivated state of human recombinant Na(V)1.

Autoradiographical imaging of PPARgamma agonist effects on PBR/TSPO binding in TASTPM mice.

Chronic inflammation is known to occur in the brains of Alzheimer's Disease (AD) patients, including the presence of activated microglia close to amyloid plaques. We utilised real time autoradiography and immunohistochemistry to investigate microglial activation and the potential anti-inflammatory effects of PPARgamma agonists in the Thy-1 APP695swe/Thy-1 PS-1.M146V (TASTPM) overexpressing transgenic mouse model of AD.

Identification of a novel 5-HT(4) receptor splice variant (r5-HT(4c1)) and preliminary characterisation of specific 5-HT(4a) and 5-HT(4b) receptor antibodies.

The human 5-hydroxytryptamine (5-HT(4)) receptor is encoded by a highly complex gene which gives rise to at least 10 distinct splice variants. However, the functional relevance of these variants is unknown. In rat, only three such variants have been identified, 5-HT(4a) (r5-HT(4a)), 5-HT(4b) (r5-HT(4b)) and 5-HT(4e) (r5-HT(4e)).

Studies on a series of potent, orally bioavailable, 5-HT(1) receptor ligands--part II.

A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different in vitro pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.

Potentiation by cholinesterase inhibitors of cholinergic activity in rat isolated stomach and colon.

Acetylcholinesterase (AChE) inhibitors stimulate gastrointestinal (GI) motility and are potential treatments of conditions associated with inadequate GI motility. The ability of itopride to facilitate neuronally (predominantly cholinergic) mediated contractions of rat isolated stomach, evoked by electrical field stimulation (EFS), has been compared with other cholinesterase inhibitors and with tegaserod, a clinically effective prokinetic and non-selective 5-HT(4) receptor agonist which also facilitates GI cholinergic function. Neostigmine greatly increased EFS-evoked contractions over a narrow concentration range (0.

AMN082, an allosteric mGluR7 agonist that inhibits afferent glutamatergic transmission in rat basolateral amygdala.

Glutamatergic neurotransmission has been implicated in the pathophysiology of psychiatric disorders, such as anxiety and depression. The possible contribution of group III metabotropic glutamate receptors has been poorly investigated, due to the lack of selective pharmacological tools. However, a selective agonist of mGLUR7, AMN082 has been identified recently, and shown to act through an allosteric mechanism in recombinant cells expressing the receptor.