Blockade of cannabinoid (CB1) receptors by 141716 selectively antagonizes drug-induced reinstatement of exploratory behaviour in gerbils.

Rationale: A cannabinoid hypothesis of schizophrenia has been proposed according to which cognitive dysfunction could be associated with dysregulation of an endogenous cannabinoid system.

Objective: The present study investigated whether SR 141716, a selective CB1 receptor antagonist, was able to reduce the hyperactivity induced in gerbils by various stimulant drugs known to produce or exacerbate schizophrenic symptoms.

Methods: Cocaine, d-amphetamine, morphine, and Win 55212-2 were administered intraperitoneally (IP) either immediately before placing the animals in the test apparatus (non-habituated gerbils) or after a 2- to 3-h habituation period in the actimeter (habituated gerbils).

Effects of SR140333, a selective non-peptide NK1 receptor antagonist, on trigemino-thalamic nociceptive pathways in the rat.

Trigeminal stimulation of C-fibers increased c-fos expression within the trigeminal nucleus caudalis (NtV) and thalamic neuronal activity which both reflect the transmission of a nociceptive message. We examined the effects on both these phenomena of the selective NK1 and NK2 receptor antagonists, SR140333 and SR48968. SR140333 (0.

SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor.

Based on both binding and functional data, this study introduces SR 144528 as the first, highly potent, selective and orally active antagonist for the CB2 receptor. This compound which displays subnanomolar affinity (Ki = 0.6 nM) for both the rat spleen and cloned human CB2 receptors has a 700-fold lower affinity (Ki = 400 nM) for both the rat brain and cloned human CB1 receptors.

Biochemical and pharmacological activities of SR 144190, a new potent non-peptide tachykinin NK2 receptor antagonist.

(R)-3-(1-[2-(4-benzoyl-2-(3,4-difluorophenyl)-morpholin-2-yl)- ethyl]-4-phenylpiperidin-4-yl)-1-dimethylurea (SR 144190) is a new non-peptide antagonist of tachykinin NK2 receptors. SR 144190 potently and selectively inhibited neurokinin A binding to NK2 receptors from various species, including humans. In in vitro functional assays, it was a potent, selective and competitive antagonist of NK2 receptors with apparent affinities (pA2 values) between 9.

Tachykinin-induced contractions of the guinea pig ileum longitudinal smooth muscle: tonic and phasic muscular activities.

In vitro tachykinin-induced contractions of guinea pig ileum longitudinal smooth muscle were investigated under isometric conditions by using selective agonists ([Sar9,Met(O2)11]substance P, [Nle10]neurokinin A-(4-10), senktide) and antagonists (SR 140333, SR 48968, SR 142801), respectively, for the tachykinin NK1, NK2, and NK3 receptors. [Sar9,Met(O2)11]Substance P (10 nM) induced a tonic contraction with superimposed phasic contractions. Both tonic and phasic muscular activities were completely abolished by SR 140333 (10 nM) and were not modified by SR 142801 (10 nM).

Pharmacological characterization of SR 142801: a new non-peptide antagonist of the neurokinin NK-3 receptor.

Pharmacological and biochemical assays were performed to characterize SR 142801, a new NK-3 receptor antagonist, and its [R]-enantiomer, SR 142806. The compounds were tested (1) in the guinea pig isolated ileum stimulated with [MePhe7]NKB (NK-3 system) in order to evaluate onset and duration of action and to estimate the apparent affinity of the antagonist in terms of pA2 at 140 min after application; (2) in 6 selected monoreceptor systems, the rabbit (rb) vena cava for the NK-1rb receptor, the rabbit pulmonary artery and the hamster (hs) urinary bladder for the NK-2rb and NK-2hs receptors, the rat (r) portal vein for the NK-3r receptor, and in two multireceptor systems adequately treated with NK-1 or NK-2 receptor antagonists to obtain monoreceptor-mediated biological responses (the rat urinary bladder treated with SR 48968 for evaluating the NK-1r and the guinea pig-gp-ileum treated with CP-99994 for measuring the antagonist affinity on the NK-3gp receptor), in order to evaluate the antagonist selectivity, and (3) in various plasma membrane preparations containing NK-3-binding sites from rats, guinea pigs, and man. The data presented indicate that SR 142801 is a potent, fairly selective non-peptide antagonist of the functional (pA2 9.

Characterization and distribution of binding sites for [3H]-SR 141716A, a selective brain (CB1) cannabinoid receptor antagonist, in rodent brain.

SR 141716A belongs to a new class of compounds (diarylpyrazole) that inhibits brain cannabinoid receptors (CB1) in vitro and in vivo. The present study showed that [3H]-SR 141716A binds with high affinity (Kd=0.61 +/- 0.

Biochemical and pharmacological characterisation of SR141716A, the first potent and selective brain cannabinoid receptor antagonist.

SR141716A is a selective, potent and orally active antagonist of the brain cannabinoid receptor with a long duration of action. This compound shows high affinity for the central cannabinoid receptor (Ki = 2 nM), displays low affinity for the peripheral cannabinoid receptor (Ki > 1000 nM). In vitro, SR141716A antagonizes the inhibitory effects of cannabinoid receptor agonists on both mouse vas deferens contractions and dopamine-stimulated adenylyl cyclase activities in rat brain membranes.

Immunopharmacological profile of SR 31747: in vitro and in vivo studies on humoral and cellular responses.

In our preceding paper, we demonstrated that both human and rat lymphocytes possess saturable high-affinity binding sites for the new sigma ligand SR 31747. Here we investigate the potential activity of this ligand on immune responses. In vitro, our study shows that SR 31747 exerts a concentration- and time-dependent inhibition of proliferative response to mitogens on mouse and human lymphocytes without affecting cell viability.

Allosteric modulation of peripheral sigma binding sites by a new selective ligand: SR 31747.

The interactions of a new compound SR 31747 with sigma sites were examined in rat spleen membranes and in human peripheral blood leukocytes (PBL). Nanomolar concentrations of SR 31747 selectively inhibited in a non-competitive manner the binding of the prototypic sigma ligands [3H](+)-pentazocine, [3H](+)-3PPP and [3H]DTG on rat spleen membranes. Characterization of SR 31747 binding sites using [3H]SR 31747 as a ligand showed that this compound binds reversibly, with high affinity to one class of sites on rat spleen membranes (Kd 0.

Evidence for a common molecular mode of action for chemically distinct nonpeptide antagonists at the neurokinin-1 (substance P) receptor.

The molecular mechanism of action of three chemically distinct nonpeptide antagonists, SR 140,333, FK 888, and RP 67,580, was compared with that of the previously characterized compound CP 96,345, using a series of chimeric constructs between their common target, the rat neurokinin (NK)-1 (substance P) receptor, and the homologous nonresponsive NK-3 (NKB) receptor. The ability of all four nonpeptide compounds to displace radiolabeled substance P from the NK-1 receptor and their ability to inhibit the peptide-induced increase in inositol phosphate turnover were critically dependent on structural elements located in an area from the middle of the second extracellular loop through transmembrane segments V and VI to the middle of the third extracellular loop of the NK-1 receptor. Dissection of the domain around the outer part of transmembrane segments V and VI into smaller segments demonstrated that the individual nonpeptide antagonists, in agreement with their distinct chemical structures, were dependent on different subepitopes within the common putative binding domain.

Neuropharmacological characterization of SR 140333, a non peptide antagonist of NK1 receptors.

SR 140333 (1-[2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl) piperidin-3-yl]ethyl]-4-phenyl-1-azonia-bicyclo[2.2.2]octane , chloride), a potent non peptide ligand of the substance P (SP) NK1 receptor subtype with high affinity for NK1 receptors from both rat cortical membranes and human IM9 cells (Ki = 0.

Identification of binding sites for SR 46349B, a 5-hydroxytryptamine2 receptor antagonist, in rodent brain.

SR 46349B belongs to a new class of compounds (propenone oxime ether derivative) that inhibit 5-hydroxytryptamine (HT)2 receptors in vitro and in vivo. (3H) SR 46349B has been shown to bind with high affinity (Kd = 1.20 nM) to a single class of sites in rat prefrontal cortical membranes.

Two nonpeptide tachykinin antagonists act through epitopes on corresponding segments of the NK1 and NK2 receptors.

The molecular mechanism of action for two chemically distinct and highly selective, nonpeptide antagonists, CP-96,345 and SR-48,968, was studied by development of a series of chimeric constructs between their respective target receptors, the NK1 (substance P) and NK2 (neurokinin A) receptors. The binding affinities of the natural peptide ligands, substance P and neurokinin A, were not affected by exchanging almost the entire C-terminal half of the NK1 receptor with the corresponding segment of the NK2 receptor. In contrast, it was found that transfer from the NK2 to the NK1 receptor of a segment corresponding to transmembrane segment VI, the amino-terminal half of transmembrane segment VII, and the connecting extracellular loop 3 completely switched the susceptibility for the nonpeptide antagonists.

Up-regulation of 5-HT2 receptors in the rat brain by repeated administration of SR 46349B, a selective 5-HT2 receptor antagonist.

Chronic administration (twice a day for three days and on the morning of the fourth day) of SR 46349B (trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3-(2-fluoroph enyl)propen-1- yl]phenol hemifumarate) (10 mg/kg, orally), a selective 5-HT2 receptor antagonist, caused 24 h later a marked increase (+42%) of the maximum binding capacity of [3H]ketanserin in rat brain cortical membranes without change in its affinity constant. Further, administration of the 5-HT2 receptor agonist, (+/-)-DOI((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) (1 mg/kg, i.p.

The NK2 receptor antagonist SR48968 inhibits thalamic responses evoked by thermal but not mechanical nociception.

Extracellular recordings were made in the thalamic posterior nuclear group of anesthetized rats to study the effects of SR48968, a non-peptide NK2 receptor antagonist, on the responses evoked by thermal or mechanical nociceptive cutaneous stimulation. SR48968 (0.125-0.

Neuropharmacological profile of a novel and selective ligand of the sigma site: SR 31742A.

The biochemical, electrophysiological and behavioural effects of SR 31742A, a novel and selective ligand of sigma sites in brain, labelled with (+)-[3H]3PPP (Ki = 5.3 +/- 0.3 nM), were investigated in rodents and compared with those of DA antagonists having (haloperidol) or not (spiroperidol) a high affinity for sigma sites.

Characterization of the binding sites of [3H]SR 48968, a potent nonpeptide radioligand antagonist of the neurokinin-2 receptor.

[3H]SR 48968, a radiolabeled nonpeptide antagonist of NK-2 receptor, has been tested in ligand-receptor binding assays using rat duodenum, hamster urinary bladder and guinea pig ileum membranes. [3H]SR 48968 bound to a single class of high affinity binding sites. Its affinity was slightly species-dependent.

Turning behavior induced in mice by a neurokinin A receptor agonist: stereoselective blockade by SR 48968, a non-peptide receptor antagonist.

The intrastriatal injection of [Nle10]-NKA(4-10), a neurokinin A agonist, (0.05-5 ng/mouse) elicited vigorous contralateral rotations. This behavior was dose-dependently antagonized by SR 48968 (ED50: 0.

Repeated administration of SR 46349B, a selective 5-hydroxytryptamine2 antagonist, up-regulates 5-hydroxytryptamine2 receptors in mouse brain.

Adaptive changes in 5-hydroxytryptamine (5-HT)2 receptors were investigated in mice after repeated administration of SR 46349B, a potent, selective, and competitive 5-HT2 receptor antagonist (Kl = 0.72 +/- 0.05 nM).

Effects on the isolated human bronchus of SR 48968, a potent and selective nonpeptide antagonist of the neurokinin A (NK2) receptors.

Tachykinins produce concentration-dependent contraction of the human isolated bronchus by stimulation of receptors that belong to the NK2 type. The aim of this study was to investigate the inhibitory effects of a new, potent, and selective nonpeptide antagonist of the neurokinin A (NKA) (NK2) receptors, SR 48968 [(S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3,4-dichlorophenyl) butyl]benzamide] on human isolated airways. Our experiments were performed on human isolated bronchi obtained from patients with lung cancer.

Biochemical and pharmacological properties of SR 46349B, a new potent and selective 5-hydroxytryptamine2 receptor antagonist.

A new potent, selective and p.o. active serotonergic [5-hydroxytryptamine (5-HT2)] receptor antagonist, SR 46349B [trans, 4-([3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-flurophenyl++ +)propen-1-yl]phenol hemifumarate) has been characterized by a series of "in vitro" and "in vivo" methods.

Neurokinin A (NK2) receptor revisited with SR 48968, a potent non-peptide antagonist.

SR 48968, a new non-peptide antagonist of NK2 receptors, has been tested in a variety of isolated smooth muscle preparations from rats, guinea pigs, rabbits, hamsters and men, in order to assess its selectivity for NK2 receptors as well as its competitivity and specificity. The compound has been found to be inactive as a stimulant or relaxant in all preparations but to exert a potent, competitive antagonism, particularly in tissues obtained from rabbits (pA2 9.8-10.

A potent and selective non-peptide antagonist of the neurokinin A (NK2) receptor.

SR 48968 is a potent and selective non-peptide antagonist of the neurokinin A (NK2) receptor. SR 48968 selectively inhibited neurokinin A binding to its receptor and was a competitive antagonist of neurokinin A-mediated contraction of different isolated smooth muscle preparations from various species including human. In vivo, the compound inhibited the bronchoconstriction induced by neurokinin A in guinea pigs.

Magnesium-deficient hairless rat: spleen cells mitogenic responses and variations in hormonal status.

Hairless rats with dermatosis induced with a poor magnesium diet were previously shown to bear biochemical and immunological abnormalities. It was therefore felt of interest to investigate the spleen cells proliferative responses from these rats, both in the rash and the remission phases, when testosterone and parathormone plasma levels were also determined. Results showed that proliferative responses to mitogens and PTH levels were inversely related to the intensity of the dermatosis, whereas testosterone levels were more or less decreased.