Benzodioxoles: novel cannabinoid-1 receptor inverse agonists for the treatment of obesity.

The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats.

Effects of rimonabant, a cannabinoid CB1 receptor ligand, on energy expenditure in lean rats.

Objective: To determine the effect of rimonabant on energy expenditure (O2 consumption) in rats at different metabolic states and in cannabinoid CB1 receptor-deficient (CB1R-/-) mice.

Design: Animals were exposed to light-dark cycles and fed only during dark cycles. Rimonabant or vehicle was administered together with food (absorptive), following overnight feeding (postabsorptive) or following a whole day of no food (fasting).

Asymmetric synthesis and receptor pharmacology of the group II mGlu receptor ligand (1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid-HYDIA.

The asymmetric synthesis and receptor pharmacology of (1S,2R,3R,5R,6S)-2-amino-3-Hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (+)-9 (HYDIA) and a few of its O-alkylated derivatives are described.

Identification of 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT2C receptor agonists.

Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT(2) receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT(2C) receptor agonists.

1-Benzyloxy-4,5-dihydro-1H-imidazol-2-yl-amines, a novel class of NR1/2B subtype selective NMDA receptor antagonists.

Screening of the Roche compound depository led to the identification of (1-benzyloxy-4,5-dihydro-1H-imidazol-2-yl)-butyl amine 4, a structurally novel NR1/2B subtype selective NMDA receptor antagonist. The structure-activity relationships developed in this series resulted in the discovery of a novel class of potent and selective NMDA receptor blockers displaying activity in vivo.

4-(3,4-dihydro-1H-isoquinolin-2yl)-pyridines and 4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolines as potent NR1/2B subtype selective NMDA receptor antagonists.

A series of 4-(3,4-dihydro-1H-isoquinolin-2yl)-pyridines and analogous quinolines was prepared and evaluated as NR1/2B subtype selective NMDA receptor antagonists. 2-Hydroxyalkylamino substitution combines high affinity with selectivity (vs alpha1 and M1 receptors) and activity in vivo.

2-(3,4-Dihydro-1H-isoquinolin-2yl)-pyridines as a novel class of NR1/2B subtype selective NMDA receptor antagonists.

Recently, we disclosed 4-aminoquinolines as structurally novel NR1/2B subtype selective NMDA receptor antagonists. We would now like to report our findings on structurally related pyridine analogues. The SAR developed in this series resulted in the discovery of high affinity antagonists which are selective (vs alpha1 and M1 receptors) and active in vivo.

New anti-MRSA and anti-VRE carbapenems; synthesis and structure-activity relationships of 1beta-methyl-2-(thiazol-2-ylthio)carbapenems.

Discovery of novel antimicrobial agents effective against infections caused by drug-resistant pathogens is an important objective. In order to find a new parenteral carbapenem antibiotic, which has potent antibacterial activity especially against methicillin-resistant staphylococci, vancomycin-resistant enterococci and penicillin-resistant Streptococcus pneumoniae, a series of 1beta-methylcarbapenems with thiazol-2-ylthio groups at the C-2 position have been synthesized. Structure-activity relationships were investigated which led to SM-197436 (27), SM-232721 (44) and SM-232724 (41), being selected for further evaluation.

Pharmacological characterization of Ro 63-1908 (1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol), a novel subtype-selective N-methyl-D-aspartate antagonist.

Ro 63-1908, 1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol, is a novel subtype-selective N-methyl-D-aspartate (NMDA) antagonist that has been characterized in vitro and in vivo. Ro 63-1908 inhibited [(3)H]dizocilpine ((3)H-MK-801) binding in a biphasic manner with IC(50) values of 0.002 and 97 microM for the high- and low-affinity sites, respectively.

4-Aminoquinolines as a novel class of NR1/2B subtype selective NMDA receptor antagonists.

Screening of the Roche compound library led to the identification of 4-aminoquinoline 4 as structurally novel NR1/2B subtype selective NMDA receptor antagonist. The SAR which was developed in this series resulted in the discovery of highly potent and in vivo active blockers.

Discovery of (R)-1-[2-hydroxy-3-(4-hydroxy-phenyl)-propyl]-4-(4-methyl-benzyl)-piperidin-4-ol: a novel NR1/2B subtype selective NMDA receptor antagonist.

Starting from Ro-25-6981 as a lead compound, highly potent and selective NR1/2B subtype selective NMDA receptor antagonists, with low activity at alpha(1) adrenergic receptors were developed.

Investigation of stretching behaviour induced by the selective 5-HT6 receptor antagonist, Ro 04-6790, in rats.

1. The present study examined the effects of the selective 5-HT6 receptor antagonist 4-amino-N-(2, 6 bis-methylamino-pyrimidin-4-yl)-benzene sulphonamide (Ro 04-6790) on locomotor activity and unconditioned behaviour in male Sprague Dawley rats (230-300 g). 2.

The putative 5-ht6 receptor: localization and function.

Until recently, the majority of actions of the neurotransmitter 5-hydroxytryptamine (5-HT) were generally believed to be mediated by members of the 5-HT1, 5-HT2, 5-HT3 and 5-HT4 receptor families. The application of molecular cloning techniques has revealed the existence of gene products encoding several novel, putative 5-HT receptors for which little or no prior pharmacological or functional data presently exist. The present challenge to pharmacologists is to determine the physiological relevance of these gene products, establish whether or not they function as endogenous receptors, find selective agents and determine potential therapeutic uses of these compounds.

Involvement of 5-HT6 receptors in nigro-striatal function in rodents.

4-Amino-N-(2,4 bis-methylamino-pyrimidin-4-yl) benzene sulphonamide (Ro 04-6790) is a potent, selective and competitive antagonist for the 5-HT6 receptor which can be detected in the cerebro-spinal fluid (CSF) of rats following intraperitoneal administration. Since 5-HT6 receptor mRNA and 5-HT6 receptor-like immunoreactivity have been shown to be present in the striatum, the purpose of the present study was to evaluate the effect of 5-HT6 receptor antagonism on haloperidol- and SCH 23390-induced catalepsy in mice and on the turning behaviour of rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle. Ro 04-6790 (3, 10 and 30 mg kg(-1) i.

The 5-hydroxytryptamine6 receptor-selective radioligand [3H]Ro 63-0563 labels 5-hydroxytryptamine receptor binding sites in rat and porcine striatum.

Ro 63-0563 [4-amino-N-(2,6 bis-methylamino-pyridin-4-yl)-benzene sulfonamide] is a high affinity 5-hydroxytryptamine6 (HT6) receptor antagonist with more than 100-fold selectivity for the 5-HT6 receptor compared with 69 other receptors and binding sites. The present study describes the properties of [3H]Ro 63-0563, the first selective 5-HT6 receptor radioligand. Specific binding of [3H]Ro 63-0563 (nonspecific binding defined in the presence of 10 microM methiothepin) to recombinant rat and human 5-HT6 receptors was saturable, rapid, and reversible with equilibrium dissociation constants (Kd) of 6.

Characterization of Ro 04-6790 and Ro 63-0563: potent and selective antagonists at human and rat 5-HT6 receptors.

1. This study describes the in vitro characterization of two potent and selective 5-HT6 receptor antagonists at the rat and human recombinant 5-HT6 receptor. 2.

Correlation between 5-HT7 receptor affinity and protection against sound-induced seizures in DBA/2J mice.

Audiogenic seizures can be induced in DBA/2J mice following intense auditory stimulation. A number of neurotransmitters, including 5-hydroxytryptamine (5-HT), are believed to be involved in mediating this effect since it has been shown previously that depletion of 5-HT or blockade of 5-HT receptors protects DBA/2J mice from these audiogenic seizures. The present study was undertaken to determine whether antagonism of the newly identified 5-HT7 receptor may protect DBA/2J mice from audiogenic seizures by attempting to correlate in vivo potency of compounds with their affinity at the 5-HT7 receptor.

Pharmacologic evaluation of the discriminative stimulus of metachlorophenylpiperazine.

A pharmacologic analysis of the discriminative stimulus of metachlorophenylpiperazine (mCPP) is reported. mCPP and m-trifluoromethylphenylpiperazine generalised, whereas 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole, 6-chloro-2-(1-piperazinyl)-pyrazine, and mesulergine partially generalised to the mCPP discriminative cue. However, although mianserin, methiothepin, ritanserin, mesulergine and N-(1-methyl-5'-indolyl)-N'-(3-pyridyl)urea hydrochloride (SB 200646) all antagonised the effect of 5-hydroxytryptamine (5-HT) on IP3 formation in the rat choroid plexus, they failed to antagonise the mCPP response in the drug discrimination studies.

Effects of altered 5-ht6 expression in the rat: functional studies using antisense oligonucleotides.

The purpose of the present study was to determine whether the 5-ht6 receptor is functionally expressed in the rat brain by blocking its translation from mRNA with treatments of phosphorothioate antisense oligonucleotides. Rats were treated with either saline, antisense (AO) or scrambled oligonucleotides (SO) for 4 days. Treatment with AO reduced the number of [3H]LSD binding sites in the frontal lobes by 30% but had no significant effect on the number of 5-HT1A and 5-HT2A receptor binding sites in the cortex of the rats.

Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor.

A heptadecapeptide was identified and purified from porcine brain tissue as a ligand for an orphan heterotrimeric GTP-binding protein (G protein)-coupled receptor (LC132) that is similar in sequence to opioid receptors. This peptide, orphanin FQ, has a primary structure reminiscent of that of opioid peptides. Nanomolar concentrations of orphanin FQ inhibited forskolin-stimulated adenylyl cyclase activity in cells transfected with LC132.

Determination of the role of the 5-ht6 receptor in the rat brain: a study using antisense oligonucleotides.

The purpose of the present study was to determine possible physiological functions of the 5-ht6 receptor using antisense oligonucleotides (AOs) in male rats. Repeated intracerebroventricular treatment with AOs but not with a scrambled form of the antisense sequence (SO) gave rise to a specific behavioral syndrome of yawning, stretching and chewing and caused a 30% reduction in the number of [3H]-lysergic acid diethylamide binding sites (measured in the presence of 300 nM spiperone). Neither sequence, however, had any effect on other parameters measured (e.

Identification of 5-hydroxytryptamine7 receptor binding sites in rat hypothalamus: sensitivity to chronic antidepressant treatment.

Due to the high level of expression of mRNA for the 5-hydroxytrytamine (5-ht7) receptor in the hypothalamus and the high affinity of 5-HT for this receptor, [3H]5-HT binding was performed in rat hypothalamus to determine whether 5-ht7 receptor binding sites are present in animal tissue. [3H]5-HT binding was performed in the presence of 100 nM pindolol, which is inactive at 5-ht7 receptors but prevents the binding of [3H]5-HT to 5-HT1A and 5-HT1B receptor binding sites. Under these conditions, [3H]5-HT bound to a binding site with an affinity of 1.

An investigation into the discriminative stimulus and reinforcing properties of the CCKB-receptor antagonist, L-365,260 in rats.

The discriminative stimulus properties of the selective CCKB-receptor antagonist, L-365,260 were evaluated in rats trained to discriminate diazepam (2 mg/kg) or morphine (5 mg/kg) from vehicle, using a two-lever food reinforced technique. In the diazepam drug discrimination, the benzodiazepine-receptor agonist FG8205 (0.063-2 mg/kg) produced dose-related drug associated responding, whereas L-365,260 (0.