Optimization of Novel α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulators and the Discovery of a Preclinical Development Candidate Molecule (RGH-560).

During optimization of a previously identified lead compound, attempts were made to optimize the reactive indole structural element, the suboptimal metabolic stability, as well as the low kinetic solubility. It was concluded that the indole was important for activity. With the aim of further improvements, more thorough modifications were also carried out.

Discovery of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor: Scaffold hopping approach.

The paper focuses on the scaffold hopping-based discovery and characterization of novel nicotinic alpha 7 receptor positive modulator (α7 nAChR PAM) ligands around the reference molecule (A-867744). First, substantial efforts were carried out to assess the importance of the various pharmacophoric elements on the in vitro potency (SAR evaluation) by chemical modifications. Subsequently, several new derivatives with versatile, heteroaromatic central cores were synthesized and characterized.

Discovery and Preclinical Characterization of 3-((4-(4-Chlorophenyl)-7-fluoroquinoline-3-yl)sulfonyl)benzonitrile, a Novel Non-acetylenic Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator for Psychiatric Indications.

Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as a potential pharmacotherapy for a number of psychiatric diseases, including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore.

Scopolamine provocation-based pharmacological MRI model for testing procognitive agents.

There is a huge unmet need to understand and treat pathological cognitive impairment. The development of disease modifying cognitive enhancers is hindered by the lack of correct pathomechanism and suitable animal models. Most animal models to study cognition and pathology do not fulfil either the predictive validity, face validity or construct validity criteria, and also outcome measures greatly differ from those of human trials.

Vascular action as the primary mechanism of cognitive effects of cholinergic, CNS-acting drugs, a rat phMRI BOLD study.

Concordant results of functional magnetic resonance imaging (fMRI) and behavioral tests prove that some non-blood-brain barrier-penetrating drugs produce robust central nervous system (CNS) effects. The anticholinergic scopolamine interferes with learning when tested in rats, which coincides with a negative blood-oxygen-level-dependent (BOLD) change in the prefrontal cortex (PFC) as demonstrated by fMRI. The peripherally acting butylscopolamine also evokes a learning deficit in a water-labyrinth test and provokes a negative BOLD signal in the PFC.

Efflux transport of serum amyloid P component at the blood-brain barrier.

Serum amyloid P component (SAP), a member of the innate immune system, does not penetrate the brain in physiological conditions; however, SAP is a stabilizing component of the amyloid plaques in neurodegenerative diseases. We investigated the cerebrovascular transport of human SAP in animal experiments and in culture blood-brain barrier (BBB) models. After intravenous injection, no SAP could be detected by immunohistochemistry or ELISA in healthy rat brains.

Discovery of cariprazine (RGH-188): a novel antipsychotic acting on dopamine D3/D2 receptors.

Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide type dopamine D(3)/D(2) compound (1) led to a series of new piperazine derivatives having affinity to both dopamine D(3) and D(2) receptors. Several members of this group showed excellent pharmacokinetic and pharmacodynamic properties as demonstrated by outstanding activities in different antipsychotic tests. The most promising representative, 2m (cariprazine) had good absorption, excellent brain penetration and advantageous safety profile.

Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents.

We investigated the in vivo effects of orally administered cariprazine (RGH-188; trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-N',N'-dimethyl-urea), a D(3)/D(2) dopamine receptor partial agonist with ∼10-fold preference for the D(3) receptor. Oral bioavailability of cariprazine at a dose of 1mg/kg in rats was 52% with peak plasma concentrations of 91ng/mL. Cariprazine 10mg/kg had good blood-brain barrier penetration, with a brain/plasma AUC ratio of 7.

Effects of 5-HT6 antagonists, Ro-4368554 and SB-258585, in tests used for the detection of cognitive enhancement and antipsychotic-like activity.

5-Hydroxytryptamine 6 (5-HT6) receptors are involved in learning and memory processes and are discussed as promising targets for the treatment of cognitive impairment in central nervous system disorders. A number of 5-HT6 antagonists are currently in the clinical development for schizophrenia and Alzheimer's disease (AD). There is some discrepancy regarding cognitive efficacy in subjects, and only limited data are available on the role of the 5-HT6 receptor in animal models of psychosis.

Chemical and biological investigation of cyclopropyl containing diaryl-pyrazole-3-carboxamides as novel and potent cannabinoid type 1 receptor antagonists.

Obesity is a major clinical problem in the western world, and many molecular targets have been explored in the search for effective therapeutic agents. One of these, antagonism of the cannabinoid 1 (CB1) receptor, rose to prominence following reports demonstrating the positive modulation of food intake by the CB1 antagonist, rimonabant (3) (SR141716A). In the present study, various diaryl-pyrazole derivatives containing cycloalkyl building blocks were synthesized and tested for CB1 receptor binding affinities.

Subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity results in favourable antipsychotic-like activity in rodent models: II. behavioural characterisation of RG-15.

RG-15 (trans-N-[4-[2-[4-(3-cyano-5-trifluoromethyl -phenyl) -piperazine -1 -yl] -ethyl] -cyclohexyl] -3 -pyridinesulfonic amide dihydro-chloride), is a highly selective dopamine D3/D2 receptor antagonist with subnanomolar affinity for the D3 receptor and nanomolar affinity for the D2 receptor. We found that RG-15 showed a good oral bioavailability (54%) and high brain levels (approx. 900 ng/g) in rats and demonstrated antipsychotic efficacy in amphetamine-induced hyperactivity and conditioned avoidance response tests in rats, yielding ED50 (median effective dose) values of 8.

Synthesis and evaluation of 2'-hydroxyethyl trans-apovincaminate derivatives as antioxidant and cognitive enhancer agents.

A series of trans-2'-hydroxyethyl and 2'-acyloxyethyl apovincaminates 4b- f and 7b- f has been synthesized and evaluated for their antioxidant and antiamnesic effects. The new esters were prepared from 4a and 7a ethyl esters or from the corresponding carboxylic acid sodium salt. For starting materials 11a, b, a new stereoselective trans-reduction was elaborated.

Novel sulfonamides having dual dopamine D2 and D3 receptor affinity show in vivo antipsychotic efficacy with beneficial cognitive and EPS profile.

A novel series of arylsulfonamides was prepared either by automated parallel or by traditional solution-phase synthesis. Several members of this compound library were identified as high-affinity dopamine D3 and D2 receptor ligands. The most interesting representative, compound 2, showed potent antipsychotic behaviour coupled with a beneficial cognitive and EPS profile.

Serum amyloid P component induces TUNEL-positive nuclei in rat brain after intrahippocampal administration.

Serum amyloid P component (SAP)-induced neuronal apoptosis has been demonstrated on the primary culture of embryonic rat cerebral cortex in vitro. Here we present pieces of evidence that cell death is also induced by serum amyloid P component in living rat brain similarly to that in cell culture. Intrahippocampally administered SAP diffuses from the site of injection to the cortical and subcortical area of the rat brain and enters the cells of brain tissue in 1 week.

Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats.

Rationale: The dopamine D3 receptor has been extensively studied in animal models of drug abuse and psychosis; however, less is known on its possible role in cognitive functions.

Objectives: This study investigated the effects of different D3 antagonists and a partial agonist on spatial learning performance in a water labyrinth test.

Methods: Rats had to swim through a labyrinth system by making correct directional turns at three choice-points.

Hypoxia-induced sleep disturbance in rats.

The effects of varying degrees of hypoxia on sleep-wake organization were studied in rats prepared for chronic electrophysiological recording. The influence of Piracetam (75, 50, and 500 mg/kg, i.p.

Effects of thyrotropin-releasing hormone and its analogue L-6-ketopiperidine-2-carbonyl-leucyl-L-prolin-amide on behaviour and electroencephalogram.

A comparative dose-response investigation of thyrotropin-releasing hormone (TRH) and L-6-ketopiperidine-2-carbonyl-leucyl-L-proline-amide (RGH-2202) was carried out on rats and cats. RGH-2202 reduced the occurrence of photically evoked after-discharge in rats more significantly than TRH. Neither of the two compounds influenced the parameters of visually evoked potentials.

Learned aversion to mannitol in water-deprived rats.

Mannitol, a non-absorbent compound may suppress free drinking in rats. It was suggested that the osmotic accumulation of water in the intestine produced a satiety signal by distending the wall of the gut, which resulted in the reduction of intake. However, we never obtained this suppression during the first exposure to mannitol in water deprived rats, while subsequent administration of this compound significantly reduced the amount of the consumed fluid.