Affinity of cyamemazine metabolites for serotonin, histamine and dopamine receptor subtypes.

Animal and human pharmacological studies indicate that the antipsychotic action of cyamemazine results from blockade of dopamine D(2) receptors, its anxiolytic properties from serotonin 5-HT(2C) receptor antagonism and the low incidence of extrapyramidal side effects from a potent 5-HT(2A) receptor antagonistic action. Cyamemazine is metabolized in monodesmethyl cyamemazine and cyamemazine sulfoxide, which are not known for their affinities for serotonin, dopamine and other brain receptor types considered to mediate central nervous systems effects of drugs. Hence, metabolite affinities were determined in human recombinant receptors expressed in CHO cells (hD(2) and hD4.

Differential effects of sulphonylureas on the vasodilatory response evoked by K(ATP) channel openers.

The potency of three sulphonylureas, glibenclamide, glimepiride and gliclazide in antagonizing the vasorelaxant action of openers of adenosine triphosphate (ATP)-regulated K+ channel (KATP) was studied in vivo and in vitro in micro- and macrovessels, respectively. In the hamster cheek pouch, the vasodilatation and the increase in vascular diameter and blood flow induced by diazoxide were markedly reduced by the addition of either glibenclamide or glimepiride (0.8 microm) while they were not affected by gliclazide up to 12 microm.

An in vitro, ex vivo, and in vivo demonstration of the lipolytic effect of slimming liposomes: An unexpected alpha(2)-adrenergic antagonism.

Most of the slimming products already developed for cosmetic applications did not result from strategies that integrate whole lipolysis-regulating mechanisms. We thus focused our attention on a more complete integration of these mechanisms and we developed slimming liposomes (SLC) containing two micro-circulation activators, i.e.

Functional modulation of gamma-aminobutyric acid(A) receptors by etifoxine and allopregnanolone in rodents.

We looked for an interaction between etifoxine and the neurosteroid allopregnanolone at central gamma-aminobutyric acid (GABA(A)) receptors. Etifoxine (2 microM) did not affect the affinity of allopregnanolone (IC(50)=108 nM) for its site in preparations of Sprague-Dawley rat cerebral cortex membranes, as determined by the inhibition of [(35)S] t-butylbicyclophosphorothionate binding, a specific ligand of the GABA(A) receptor chloride channel site. Etifoxine and allopregnanolone were anticonvulsants, blocking the clonic convulsions induced by bicuculline (an antagonist of the GABA(A) receptor) in CD1 mice.

Genistein and daidzein modulate in vitro rat uterine contractile activity.

The present study investigated the effect of genistein, daidzein and estradiol on in vitro rat uterine responsiveness to oxytocin (OT) and PGF(2)alpha or luprostiol (L). In a first experiment, animals were either sham-operated (SH; n=5), or ovariectomized (OVX; n=20) and orally treated for three months with either genistein (G; n=5; 10 microg/g BW/d) or daidzein (D; n=5; 10 microg/g BW/d) or 17 alpha-ethinylestradiol (E; n=5; 23 microg/kg BW/d) or untreated (OVX; n=5). At necropsy, the basal uterine tension was lower in OVX, G and D than in SH, the highest value being measured in E.

Receptor binding profile of Otilonium bromide.

The interaction of Otilonium bromide (OB) with binding sites for 63 different receptors and ion channels in appropriate preparations has been investigated. Experiments were also performed in rat colon, the preferred tissue for OB 'in vivo' uptake after oral administration. Among the receptors investigated OB binds with sub microM affinity to muscarinic M1, M2, M4, M5 and PAF receptors and with microM affinity to the diltiazem binding site on L type Ca2+ channels.

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.

The naphtosultam derivative RP 62203 (fananserin) has high affinity for the dopamine D4 receptor.

The dopamine D4 receptor is a potential target for novel antipsychotic drugs. Most available compounds with affinity for the dopamine D4 receptor also bind to dopamine D2 receptors. This report describe the affinity of the 5-HT2A receptor antagonist RP 62203 (fananserin) for the human dopamine D4 receptor.

Lack of effect of repeated administration of milnacipran, a double noradrenaline and serotonin reuptake inhibitor, on the beta-adrenoceptor-linked adenylate cyclase system in the rat cerebral cortex.

The effects of subacute administration of the double noradrenaline and serotonin uptake inhibitor antidepressant, milnacipran, and the tricyclic antidepressant, imipramine, on radioligand binding to beta-adrenergic receptors and on beta-adrenergic agonist-stimulated adenylate cyclase activity, in the rat cerebral cortex, have been determined. Rats were injected intraperitoneally for 21 days with milnacipran (3, 10 or 30 mg/kg/day) or imipramine (10 mg/kg/day). The treatment with milnacipran up to 30 mg/kg/day did not modify either the maximum number of [3H]CGP-12177 binding sites (Bmax) or the equilibrium dissociation constant (Kd).

SR 120819A, an orally-active and selective neuropeptide Y Y1 receptor antagonist.

An orally-active antagonist of neuropeptide Y (NPY) Y1 receptors, SR 120819A, has been characterized. This compound displays highly selective and competitive affinity for rat, guinea-pig and human (Ki = 15 nM) NPY Y1 receptors. In vitro, SR 120819A blocks the inhibitory effect of NPY on adenylyl cyclase activity in human SK-N-MC cells and that of the selective Y1 agonist, [Leu31,Pro34]NPY, on rabbit vas deferens contraction (pA2 = 7.

SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor.

SR 142801 is the first potent and selective non-peptide antagonist of the tachykinin NK3 receptor. It inhibited [MePhe7]NKB binding to its receptor from various species, including humans. SR 142801 was a competitive antagonist of [MePhe7]NKB-mediated contractions of guinea-pig ileum and inhibited the acetylcholine release following the activation of the guinea-pig ileum tachykinin NK3 receptor.

Up-regulation of [3H]-des-Arg10-kallidin binding to the bradykinin B1 receptor by interleukin-1 beta in isolated smooth muscle cells: correlation with B1 agonist-induced PGI2 production.

1. Binding of the specific bradykinin B1 receptor agonist, [3H]-des-Arg10-kallidin (-KD) was investigated in smooth muscle cells (SMC) isolated from rabbit mesenteric arteries (RMA). 2.

SR141716A, a potent and selective antagonist of the brain cannabinoid receptor.

SR141716A is the first selective and orally active antagonist of the brain cannabinoid receptor. This compound displays nanomolar affinity for the central cannabinoid receptor but is not active on the peripheral cannabinoid receptor. In vitro, SR141716A antagonises the inhibitory effects of cannabinoid receptor agonists on both mouse vas deferens contractions and adenylyl cyclase activity in rat brain membranes.

In vitro and in vivo biological activities of SR140333, a novel potent non-peptide tachykinin NK1 receptor antagonist.

(S)1-(2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)pip eridin-3- yl]ethyl)-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride (SR140333) is a new non-peptide antagonist of tachykinin NK1 receptors.

Different effects of interleukin-1 on reactivity of arterial vessels isolated from various vascular beds in the rabbit.

During septic shock, arterial smooth muscle is thought to be hyporeactive to vasoconstrictors. This hyporeactivity, however, seems to be different from one vascular bed to another. Interleukin-1 (IL-1), which is released during septic shock, might play a role in the different regional vascular responses to norepinephrine.

Peripheral biological activity of SR 27897: a new potent non-peptide antagonist of CCKA receptors.

SR 27897 is a new non-peptide antagonist of CCKA receptors: 1-[[2-(4-(2-chlorophenyl)thiazol-2-yl)aminocarbonyl] indolyl] acetic acid. This compound is a potent ligand for CCKA binding sites (rat pancreatic membranes, Ki = 0.2 nM) and is highly selective (CCKB and gastrin/CCKA IC50 ratios of 800 and 5000 respectively).

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.

Interleukin-1 impairs both vascular contraction and relaxation in rabbit isolated aorta.

Incubation of rabbit aortic rings with interleukin-1 (100 U/ml) in vitro led to a depressed contractile response to norepinephrine, whether the endothelium was present or not. In both cases norepinephrine-induced contraction was restored in the presence of NG-methyl-L-arginine (300 microM), an inhibitor of nitric oxide synthesis. In interleukin-1-treated rings precontracted with norepinephrine (1 microM), the relaxing response to acetylcholine was totally suppressed independently on the presence of endothelium.

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.

Characterization of beta-adrenoceptor subtypes and indications for two cell populations in isolated bovine mesenteric lymphatic vessels.

The pharmacological characterization of beta-adrenoceptor subtypes and the identification of two cell populations were investigated in isolated bovine mesenteric lymphatic vessels. The beta-adrenoceptor agonists isoprenaline, dobutamine and salbutamol concentration dependently decreased the amplitude and the frequency of spontaneous contractions and the amplitude of electrically induced contractions. The order of potency was isoprenaline greater than salbutamol greater than dobutamine.

The role of alpha- and beta-adrenoceptors in the response to noradrenaline of lymphatic vessels isolated from the bovine mesentery.

The role of postsynaptic adrenoceptors in the spontaneous activity of isolated bovine mesenteric lymphatic vessels was characterized. Low concentrations of noradrenaline (less than 10(-6) M) increased the amplitude and the frequency of the spontaneous contractions whereas high concentrations (less than 10(-6) M) depressed the activity. beta-Adrenoceptor blockade with propranolol enhanced the stimulation by noradrenaline and suppressed the inhibition.

PK 11195, an antagonist of peripheral type benzodiazepine receptors, modulates Bay K8644 sensitive but not beta- or H2-receptor sensitive voltage operated calcium channels in the guinea pig heart.

In a partially depolarized guinea pig papillary muscle preparation, BAY K8644 stimulated voltage-operated calcium channels, promoting slow action potentials; this effect was dose-dependent over a concentration range of 3 X 10(-7) M to 3 X 10(-6) M. Isoproterenol and histamine also induced slow action potentials by stimulating beta or H2 receptors, respectively. PK 11195, the antagonist of peripheral type benzodiazepine receptors, inhibited the effect of BAY K8644, but not those of histamine or isoproterenol.