Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation.

The forebrain cholinergic system promotes higher brain function in part by signaling through the M(1) muscarinic acetylcholine receptor (mAChR). During Alzheimer's disease (AD), these cholinergic neurons degenerate, therefore selectively activating M(1) receptors could improve cognitive function in these patients while avoiding unwanted peripheral responses associated with non-selective muscarinic agonists. We describe here benzyl quinolone carboxylic acid (BQCA), a highly selective allosteric potentiator of the M(1) mAChR.

[Psychotherapy of patients with personality disorders with predominance of hypochondria].

A standard of psychotherapeutic help to patients with hypochondriac disorder developed in paranoid, schizoid, anxiety and dependent personality disorders is worked out. In this case, hypochondria is inseparable from the personality structure. Patients of investigated group (61 people) received traditional medical treatment, individual differential symptomatic psychotherapy and a short group course with a variant of the therapy by means of creative sell-expression (TCSEB) worked out by M.

A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models.

We found that 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) is a potent and selective positive allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). In Chinese hamster ovary cells expressing human mGluR5, CDPPB potentiated threshold responses to glutamate in fluorometric Ca2+ assays more than 7-fold with an EC50 value of approximately 27 nM. At 1 microM, CDPPB shifted mGluR5 agonist concentration response curves to glutamate, quisqualate, and (R,S)-3,5-dihydroxyphenylglycine 3- to 9-fold to the left.

Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo.

This report describes the discovery of the first centrally active allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). Appropriately substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides (e.g.

The glycine transporter type 1 inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine potentiates NMDA receptor-mediated responses in vivo and produces an antipsychotic profile in rodent behavior.

Glycine acts as a necessary coagonist for glutamate at the NMDA receptor (NMDAR) complex by binding to the strychnine-insensitive glycine-B binding site on the NR1 subunit. The fact that glycine is normally found in the brain and spinal cord at concentrations that exceed those required to saturate this site has led to the speculation that glycine normally saturates NMDAR-containing synapses in vivo. However, additional lines of evidence suggest that synaptic glycine may be efficiently regulated in synaptic areas by the glycine transporter type 1 (GlyT1).

Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents.

Use-dependent N-methyl-d-aspartate receptor (NMDAR) antagonists produce behaviors in human volunteers that resemble schizophrenia and exacerbate those behaviors in schizophrenic patients, suggesting that hypofunction of NMDAR-mediated neuronal circuitry may be involved in the etiology of clinical schizophrenia. Activation of the metabotropic glutamate receptor subtype 5 (mGluR5) enhances NMDAR-mediated currents in vitro. Thus, activation of mGluR5 could potentiate hypofunctional NMDARs in neuronal circuitry relevant to schizophrenia.

A nonpeptide oxytocin receptor antagonist radioligand highly selective for human receptors.

A novel, potent nonpeptide oxytocin receptor antagonist (1-(1-(2-(2,2,2-trifluoroethoxy)-4-(1-methylsulfonyl-4-piperidinyloxy) phenylacetyl)-4-piperidinyl)-3,4-dihydro-2(1H)-quinolinone) has been identified that can be labeled to high specific activity with [35S]. In binding studies, this compound exhibits sub-nanomolar affinity and a high degree of selectivity (900-1800-fold) for human oxytocin receptors compared to human vasopressin receptors. This compound appears suitable for studying the pharmacology of oxytocin receptors in human and nonhuman primate tissues, for which there is currently a paucity of highly selective tools.

Identification of a human 5-HT6 receptor variant produced by alternative splicing.

The complexity of the 5-hydroxytryptamine (5-HT) (serotonin) receptor family has been increased by the findings that isoforms or splice variants exist for subtypes such as the 5-HT2B, 5-HT2C, 5-HT4 and 5-HT7 subtypes. Further molecular biological studies in our laboratory have demonstrated that a splice variant of the 5-HT6 receptor exists in the human brain. Experiments performed using a degenerate PCR approach from human caudate cDNA revealed a 5-HT6 receptor clone with a 289 bp deletion of the region coding for transmembrane IV through the third intracellular loop.

[Psychotherapy of psychopathic patients and patients with slowly progressing schizophrenia with defensive manifestations using a method of creative self-expression].

Summarized is a several years' experience of the out-patient psychotherapy of 312 psychopathologic patients of different clinical groups manifesting defensive disorders (psychasthenic, asthenic, defensive cycloid, schizoid, epileptoid, defensive hysterical psychopathic, anankastic personalities) and patients with defensiveness due to slowly progressing schizophrenia. The described technique allowed steady remissions and compensation in 80.1% of the cases.

["Simple-minded" personality variant among chronic alcoholic patients].

The author describes a frequently encountered variant of alcoholic patients' personality with non-psychopathic premorbid features (phlegmatic kind-heartedness, faultlessness, cordiality, conscientiousness, vulnerability). The "pivot" of these features is "simple-mindedness". The peculiarities of alcoholism hypnotic states ("obliterated" somnambulism) and treatment in these patients according to their individual protective-psychological mechanisms are shown.

[Forms of hypnotic somnambulism according to their clinical basis].

Three forms of hypnotic somnambulism were distinguished clinically: classical somnambulism in patients with hysterical neurosis on a juvenile-unstable basis (42 cases); sensual-lucid somnambulism in patients with hysterical neurosis on a primitive personality basis (46 cases) and sensual-split somnambulism in patients with pseudoneurotic schizophrenia with a hysteroid clinical picture (58 cases). The differential diagnostic importance of such forms of somnambulism is stressed.

[A clinico-neurophysiologic study of psychasthenic psychopathies].

The authors studied 25 patients with psychasthenic psychopathy who according to the clinical picture were divided into 2 groups: psychasthenics proper and anankasts. The results of the study permitted to detect some correlations between the clinical traits and neurophysiological interconnections between the cortex and nonspecific subcortical structures. Such correlations were made on the basis of a multicomponent structure of the orientation reaction (especially the EEG reactions and SGR) to stimula of different modality and background bioelectrical activity of the brain.