LY277359 maleate: a potent and selective 5-HT3 receptor antagonist without gastroprokinetic activity

Several 5-hydroxytryptamine (5-HT3) receptor antagonists have been described. In addition to 5-HT3 receptor antagonist activity, many of these agents also possess gastroprokinetic activity. In the present report, we identify compound LY277359 maleate as a potent, p.o. active, highly selective 5-HT3 receptor antagonist lacking gastroprokinetic effects. LY277359 maleate was a potent and selective antagonist of 2-methyl 5-HT-induced contraction in the guinea pig ileum (KB = 1.6 nM), a response mediated by activation of 5-HT3 receptors. Given both i.v. (0.0003, 0.001 and 0.003 mg/kg) and p.o. (0.01 and 0.03 mg/kg), LY277359 maleate inhibited the bradycardic response to i.v. administered 5-HT in urethane-anesthetized rats. The duration of antagonism of 5-HT-induced bradycardia persisted beyond 6 hr after p.o. administration of LY277359 maleate (0.03 mg/kg p.o.). In contrast to its potent 5-HT3 receptor antagonist activity, LY277359 maleate, in doses up to 1 mg/kg p.o., did not affect gastric emptying in rats, suggesting minimal, if any, gastroprokinetic activity of LY277359 maleate. This is in contrast to another 5-HT3 receptor antagonist, zacopride, which did produce a marked increase in gastric emptying in rats at doses of 0.1 mg/kg p.o. and higher. LY277359 maleate (0.03 and 0.1 mg/kg i.v. and 0.07, 0.1, 0.3 and 1.0 mg/kg p.o.) did have effects consistent with other 5-HT3 antagonists, to inhibit cisplatin-evoked emesis in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacology of DuP 532, a selective and noncompetitive AT1 receptor antagonist

DuP 532 (2-propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5-yl)bip hen yl- 4-yl)methyl]imidazole-5-carboxylic acid) inhibited the specific binding of [125I]angiotensin II (AII) for the subtype receptor AT1 in rat adrenal cortical membranes with an IC50 of 3.1 X 10(-9) M, but not the [125I]AII binding for the subtype AT2 sites in rat adrenal medulla tissues. It inhibited the contractile response to AII selectively and noncompetitively in the isolated rabbit aorta with a KB value of 1.1 X 10(-10) M. The selective AII antagonism was confirmed in the guinea pig ileum and the pithed rat. In conscious rats, DuP 532 inhibited the AII-induced pressor effect, aldosterone secretion, and water drinking induced by AII. In conscious renal hypertensive rats, DuP 532 decreased blood pressure with i.v. and p.o. ED30 of 0.02 and 0.21 mg/kg, respectively. The antihypertensive effect of DuP 532 at 0.3 to 3 mg/kg p.o. lasted for at least 24 hr. In conscious spontaneously hypertensive rats, DuP 532 given i.v. or p.o. at 0.3 to 3 mg/kg reduced blood pressure dose-dependently. DuP 532, at doses up to 100 mg/kg i.v., did not cause a pressor response in conscious normotensive rats, suggesting lack of agonism. DuP 532 exerted selective AII antagonism in conscious dogs. In conscious furosemide-treated dogs, DuP 532 given either at 0.3 and 1 mg/kg i.v. or at 1 to 10 mg/kg p.o. decreased blood pressure. As the AT1 receptors are responsible for AII-induced vasoconstriction, aldosterone secretion, and water drinking, our study indicates that DuP 532 is a potent, orally active, selective, and noncompetitive AT1 receptor antagonist and antihypertensive agent.     

Agonist, antagonist, and inverse agonist characteristics of TIPP (H-Tyr-Tic-Phe-Phe-OH), a selective delta-opioid receptor ligand

Recent evidence indicates that the well established delta-opioid antagonist TIPP (H-Tyr-Tic-Phe-Phe-OH) also displays agonist activity in several cellular models. Therefore, it is possible that TIPP, and structurally related compounds, might represent a novel class of opioid agonists exhibiting unique characteristics. The purpose of this study was to examine the properties of TIPP at selected points of the signal transduction pathway (i.e., receptor binding, G-protein activation, and effector regulation) in GH(3)DORT cells (GH(3) cells expressing delta-opioid receptors) and compare them with that of an established delta-opioid agonist, [D-Pen(2),D-Pen(5)]-enkephalin (DPDPE). DPDPE exhibited properties of an agonist in all assays. In contrast, TIPP demonstrated characteristics of an agonist, antagonist, or inverse agonist, depending on the step in the signal transduction cascade examined and the assay conditions employed. In receptor binding assays, the addition of guanine nucleotides and sodium ions increased the affinity of TIPP for delta-opioid receptors in both membrane preparations and digitonin-permeabilized cells, which is characteristic of an inverse agonist. In assays measuring G-protein activation, TIPP failed to stimulate guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding in membrane preparations, which is consistent with an antagonist profile. However, when using cells semi-permeabilized with digitonin, TIPP exhibited properties of an agonist, producing concentration-dependent, antagonist-reversible stimulation of [(35)S]GTPgammaS binding. Finally, in assays examining regulation of the intracellular effector adenylyl cyclase, TIPP exhibited characteristics of an agonist, producing inhibition of enzyme activity in both membrane preparations and whole cells. Therefore, although DPDPE and TIPP act similarly as agonists to regulate the intracellular effector adenylyl cyclase, they demonstrate significant differences in the signal transduction cascade preceding this final point of convergence.     

Behavioral effects of U-78875, a quinoxalinone anxiolytic with potent benzodiazepine antagonist activity.

U-78875 (3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl) imidazo[1,5-a]-quinoxalin-4(5H)-one) is a chemically novel compound with a high affinity for the benzodiazepine receptors. It has anticonflict effects in both the Vogel and Cook-Davidson models of anxiety, with a potency similar to that of diazepam (1-3 mg/kg, i.p.). In unanesthetized rats implanted with cortical electrodes for EEG recording, i.p. injections of U-78875 (3-10 mg/kg) increased the EEG power density in frequencies above 12 Hz, and decreased EEG power at lower frequencies. This EEG effect is similar to that of diazepam, and was completely antagonized by pretreatment with flumazenil. In animal models measuring central nervous system depression, U-78875 is much weaker than diazepam. It produced minimal impairment of rotarod performance in rats at doses up to 30 mg/kg, but at lower doses completely reversed the impairment from 10 mg/kg of diazepam. In rats trained to avoid shocks in a shuttle box, U-78875 (3-10 mg/kg) increased avoidance responses and antagonized the suppression of avoidance from diazepam (10 mg/kg). In the mouse one-trial passive avoidance task, pretreatment with U-78875 (1-10 mg/kg) before training produced no anterograde amnesia, but completely blocked the amnesic effect from diazepam (10 mg/kg). The diazepam antagonist potency for U-78875 is 10 to 100 times that of flumazenil. This unusual profile of mixed agonist/antagonist activities suggests U-78875 to be a unique anxiolytic agent with a minimum of central nervous system depression.     

2-furoyl-LIGRLO-amide: a potent and selective proteinase-activated receptor 2 agonist

A peptide corresponding to a proteinase-activated receptor 2 (PAR(2))-activating peptide with an N-terminal furoyl group modification, 2-furoyl-LIGRLO-NH(2), was assessed for PAR(2)-dependent and -independent biological activities. 2-Furoyl-LIGRLO-NH(2) was equally effective to and 10 to 25 times more potent than SLIGRLNH(2) for increasing intracellular calcium in cultured human and rat PAR(2)-expressing cells, respectively. In bioassays of tissue PAR(2) activity, measured as arterial vasodilation and hyperpolarization, 2-furoyl-LIGRLO-NH(2) was 10 to 300 times more potent than SLIGRL-NH(2). Unlike trans-cinnamoyl-LIGRLO-NH(2), 2-furoyl-LI-GRLO-NH(2) did not cause a prominent non-PAR(2)-mediated contraction of murine femoral arteries. In conclusion, 2-furoyl-LI-GRLO-NH(2) represents the most potent and selective activator of PAR(2) in biological systems described to date.     

Varenicline is a potent agonist of the human 5-hydroxytryptamine3 receptor

Varenicline, a widely used and successful smoking cessation agent, acts as a partial agonist at nicotinic acetylcholine receptors. Here, we explore the effects of varenicline at human and mouse 5-Hydroxytryptamine(3) (5-HT(3)) receptors. Application of varenicline to human 5-HT(3) receptors expressed in Xenopus laevis oocytes reveal it is almost a full agonist (R(max) = 80%) with an EC(50) (5.9 μM) 3-fold higher than 5-HT. At mouse 5-HT(3) receptors varenicline is a partial agonist (R(max) = 35%) with an EC(50) (18 μM) 20-fold higher than 5-HT. Displacement of the competitive 5-HT(3) receptor antagonist [(3)H]granisetron reveals similar IC(50) values for varenicline at mouse and human receptors expressed in human embryonic kidney 293 cells, although studies in these cells using a membrane potential-sensitive dye show that again varenicline is a 4- or 35-fold less potent agonist than 5-HT in human and mouse receptors, respectively. Thus the data suggest that the efficacy, but not the affinity, of varenicline is greater at human 5-HT(3) receptors compared with mouse. Docking studies provide a possible explanation for this difference, because they suggest distinct orientations of the ligand in the mouse versus human 5-HT(3) agonist binding sites. Additional binding selectivity studies in a broad panel of recombinant receptors and enzymes confirmed an interaction with 5-HT(3) receptors but revealed no additional interactions of varenicline. Therefore, activation of human 5-HT(3) receptors may be responsible for some of the side effects that preclude use of higher doses during varenicline treatment.     

Ro 19-8022, a nonbenzodiazepine partial agonist at benzodiazepine receptors: neuropharmacological profile of a potential anxiolytic.

The partial agonist at benzodiazepine receptors, Ro 19-8022, has been characterized as a putative anxiolytic drug with an improved side effect profile. This orally active compound is a representative of a quinolizinone structure class and shows potent anticonflict activity in mice and rats. It protects rodents from convulsions induced by pentylenetetrazol, N-methyl-D-aspartic acid and maximal electroshock, as well as against audiogenic seizures, with an efficacy comparable to that of the full agonist alprazolam. No appreciable sedative or motor-impairing effects could be detected up to a very high dose (100 mg/kg) in the horizontal wire test or the rotarod performance test in mice and rats and in spontaneous behavior in monkeys. Consistent with its characterization as a partial agonist, Ro 19-8022 antagonized the motor impairment induced by the full agonists diazepam or meclonazepam measured in horizontal wire and rotarod tests in rodents, and reduced flunitrazepam-induced effects in squirrel monkeys, with an efficacy comparable to that of the benzodiazepine receptor antagonist flumazenil. After subchronic administration of Ro 19-8022 to mice, antagonist-precipitated withdrawal syndrome was dramatically weaker than after alprazolam treatment, which is indicative of a lower physical dependence liability of Ro 19-8022. Pharmacodynamic effects recorded in convulsion and reversal of motor impairment tests after i.v. administration suggest a long duration of action of this compound. Taken together, such preclinical data suggest that benzodiazepine receptor partial agonists with a neurological and behavioral profile such as that of Ro 19-8022 may offer an innovative therapeutic approach to the treatment of anxiety disorders.     

CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties

The prostaglandin (PG) EP(4) receptor subtype is expressed by peripheral sensory neurons. Although a potential role of EP(4) receptor in pain has been suggested, a limited number of selective ligands have made it difficult to explore the physiological functions of EP(4) or its potential as a new analgesic target. Here, we describe the in vitro and in vivo pharmacology of a novel EP(4) receptor antagonist, N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) phenyl]ethyl}amino) carbonyl]-4-methylbenzenesulfonamide (CJ-023,423). In vitro, CJ-023,423 inhibits [(3)H]PGE(2) binding to both human and rat EP(4) receptors with K(i) of 13 +/- 4 and 20 +/- 1 nM, respectively. CJ-023,423 is highly selective for the human EP(4) receptor over other human prostanoid receptor subtypes. It also inhibits PGE(2)-evoked elevation in intracellular cAMP at the human and rat EP(4) receptors with pA(2) of 8.3 +/- 0.03 and 8.2 +/- 0.2 nM, respectively. In vivo, oral administration of CJ-023,423 significantly reduces thermal hyperalgesia induced by intraplantar injection of PGE(2) (ED(50) = 12.8 mg/kg). CJ-023,423 is also effective in models of acute and chronic inflammatory pain. CJ-023,423 significantly reduces mechanical hyperalgesia in the carrageenan model. Furthermore, CJ-023,423 significantly reverses complete Freund's adjuvant-induced chronic inflammatory pain response. Taken together, the present data indicate that CJ-023,423, a highly potent and selective antagonist of both human and rat EP(4) receptors, produces antihyperalgesic effects in animal models of inflammatory pain. Thus, specific blockade of the EP(4) receptor signaling may represent a novel therapeutic approach for the treatment of inflammatory pain.     

Identification and characterization of INCB9471, an allosteric noncompetitive small-molecule antagonist of C-C chemokine receptor 5 with potent inhibitory activity against monocyte migration and HIV-1 infection

C-C chemokine receptor 5 (CCR5) is a clinically proven target for inhibition of HIV-1 infection and a potential target for various inflammatory diseases. In this article, we describe 5-[(4-{(3S)-4-[(1R,2R)-2-ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine dihydrochloride (INCB9471), a potent and specific inhibitor of human CCR5 that has been proven to be safe and efficacious in viral load reduction in phase I and II human clinical trails. INCB9471 was identified using a primary human monocyte-based radioligand competition binding assay. It potently inhibited macrophage inflammatory protein-1β-induced monocyte migration and infection of peripheral blood mononuclear cells by a panel of R5-HIV-1 strains. The results from binding and signaling studies using incremental amounts of INCB9471 demonstrated INCB9471 as a noncompetitive CCR5 inhibitor. The CCR5 residues that are essential for interaction with INCB9471 were identified by site-specific mutagenesis studies. INCB9471 rapidly associates with but slowly dissociates from CCR5. When INCB9471 was compared with three CCR5 antagonists that had been tested in clinical trials, the potency of INCB9471 in blocking CCR5 ligand binding was similar to those of 4,6-dimethyl-5-{[4-methyl-4-((3S)-3-methyl-4-{(1R0-2-(methyloxy)-1-[4-(trifluoromethyl) phenyl]ethyl}-1-piperazingyl)-1-piperidinyl]carbonyl}pyrimidine (SCH-D; vicriviroc), 4-{[4-({(3R)-1-butyl-3-[(R)-cyclohexyl(hydroxyl)methyl]-2, 5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenyl]oxy}benzoic acid hydrochloride (873140; aplaviroc), and 4,4-difluoro-N-((1S)-3-{(3-endo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropyl)cyclohexanecarboxamide (UK427857; maraviroc). Its inhibitory activity against CCR5-mediated Ca(2+) mobilization was also similar to those of SCH-D and 873140. Further analysis suggested that INCB9471 and UK427857 may have different binding sites on CCR5. The significance of two CCR5 antagonists with different binding sites is discussed in the context of potentially overcoming drug-resistant HIV-1 strains.     

A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties

Histamine mediates its physiological function through binding to four known histamine receptors. Here, we describe the first selective antagonist of the histamine H4 receptor, the newest member of the histamine receptor family, and provide evidence that such antagonists have anti-inflammatory activity in vivo. 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ 7777120) has a K(i) of 4.5 nM versus the human receptor and a pA(2) of 8.1. It is equipotent against the human, mouse, and rat receptors. It exhibits at least 1000-fold selectivity over H1, H2, or H3 receptors and has no cross-reactivity against 50 other targets. This compound has an oral bioavailability of approximately 30% in rats and 100% in dogs, with a half-life of approximately 3 h in both species. JNJ 7777120 blocks histamine-induced chemotaxis and calcium influx in mouse bone marrow-derived mast cells. In addition, it can block the histamine-induced migration of tracheal mast cells from the connective tissue toward the epithelium in mice. JNJ 7777120 significantly blocks neutrophil infiltration in a mouse zymosan-induced peritonitis model. This model is reported to be mast cell-dependent, which suggests that the compound effect may be mediated by mast cells. These results indicate that the histamine H4 receptor plays a role in the inflammatory process. Selective H4 receptor antagonists like JNJ 7777120 may have the potential to be useful in treating inflammation in humans.     

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. Based upon binding studies with 5-HT2 receptors in rat brain cortical membranes and blockade of 5-HT-induced contractions in isolated tissues (rabbit thoracic aorta, rat jugular vein, rat caudal artery, rat uterus and guinea pig trachea), SR 46349B showed high affinity for 5-HT2 receptors. Furthermore, SR 46349B displayed moderate affinity for the 5-HT1C receptor and had no affinity for the other 5-HT1 subclass (5-HT1A, 5-HT1B or 5-HT1D), dopamine (D1 or D2), "alpha" adrenergic (alpha-1 or alpha-2), sodium and calcium channel and histamine (H1) receptors. It did not interact with histamine (H1), alpha-1 adrenergic and 5-HT3 receptors in smooth muscle preparations. No inhibition of the uptake of norepinephrine, dopamine or 5-HT was seen. Based upon blockade of pressor responses to 5-HT in pithed rats and in vivo binding studies in mice, SR 46349B was found to be a potent and p.o. active 5-HT2 receptor antagonist with a relatively long duration of action. Behavioral experiments, including mescaline- and 5-hydroxytryptophan-induced head twitches and learned helplessness, as well as sleep-waking cycle and EEG spectral parameter studies, indicated that SR 46349B has a classical 5-HT2 psychopharmacological antagonist profile.     

N-methylacetamide analog of salvinorin A: a highly potent and selective kappa-opioid receptor agonist with oral efficacy

Several preclinical studies indicate that selective kappa-opioid receptor (KOR) antagonists have antidepressant-like effects, whereas KOR agonists have opposite effects, suggesting that each might be useful in the treatment of mood abnormalities. Salvinorin A (salvA) is a valuable KOR agonist for further study due to its high potency and receptor selectivity. However, it has short lasting effects in vivo and limited oral bioavailability, probably due to acetate metabolism. We compared the in vitro receptor binding selectivity of salvA and four analogs containing an ethyl ether (EE), isopropylamine (IPA), N-methylacetamide (NMA), or N-methylpropionamide (NMP) at C-2. All compounds showed high binding affinity for the KOR (K(i) = 0.11-6.3 nM), although only salvA, EE, and NMA exhibited KOR selectivity. In a liver microsomal assay, salvA was least stable, whereas NMA and IPA displayed slower metabolic transformations. Intraperitoneal (i.p.) administration of salvA, NMA, and NMP dose-dependently elevated brain reward thresholds in the intracranial self-administration (ICSS) test, consistent with prodepressive-like KOR agonist effects. NMA and NMP were equipotent to salvA but displayed longer lasting effects (6- and 10-fold, respectively). A dose of salvA with prominent effects in the ICSS test after i.p. administration (2.0 mg/kg) was inactive after oral administration, whereas the same oral dose of NMA elevated ICSS thresholds. These studies suggest that, although salvA and NMA are similar in potency and selectivity as KOR agonists in vitro, NMA has improved stability and longer lasting actions that might make it more useful for studies of KOR agonist effects in animals and humans.     

SK&F 105494: a potent antidiuretic hormone antagonist devoid of partial agonist activity in dogs

Previous studies from our laboratory have shown that in vivo cyclooxygenase blockade in dogs unmasks the antidiuretic agonist activity associated with the vasopressin antagonist, SK&F 101926, and have revealed two new vasopressin analogs, SK&F 104146 and 105494, with greatly reduced antidiuretic agonist activity. The purpose of the present study was to characterize SK&F 104146 and SK&F 105494 for water diuretic activity (aquaretic activity) in hydropenic dogs and for antagonism of vasopressin-stimulated antidiuresis in hydrated dogs. The vasopressin receptor affinity and inhibition of vasopressin-stimulated adenylate cyclase activity in renal membranes were also studied. When administered to hydropenic dogs, SK&F 101926 (3 or 30 micrograms/kg) did not cause a water diuresis. Substitution of the dipeptide tail of SK&F 101926 with Arg7D-Arg8NH2 (SK&F 104146; 30 micrograms/kg) was associated with a reduction of urine osmolality from 1876 +/- 182 to 349 +/- 94 mOsm/kg of H2O, and an increase in free water clearance (from -0.32 +/- 0.09 to 0.06 +/- 0.09 ml/min). Replacement of the 1 to 6 disulfide bridge of SK&F 104146 with a 1 to 6 dicarba bridge (SK&F 105494; 3 micrograms/kg) was associated with a further reduction of urine osmolality (1709 +/- 281 to 210 +/- 79 mOsm/kg of H2O) and a net positive free water clearance (from -0.56 +/- 0.02 to 0.6 +/- 0.35 ml/min). In water diuretic dogs, SK&F 104146 and 105494 shifted the vasopressin dose-response for antidiuresis to the right. SK&F 105494 appeared to be 3 times more potent than SK&F 104146.(ABSTRACT TRUNCATED AT 250 WORDS)     

15R-methyl-prostaglandin D2 is a potent and selective CRTH2/DP2 receptor agonist in human eosinophils

Prostaglandin D2 (PGD2) is a mast cell-derived mediator that seems to play a role in asthma and allergic diseases. It is the only primary prostanoid to activate human eosinophils, which it accomplishes through the DP2 receptor/chemoattractant receptor-homologous molecule expressed on T helper cell type 2 (Th2) cells (CRTH2). In addition, PGD2 has both pro- and anti-inflammatory effects via the adenylyl cyclase-coupled DP1 receptor. To attempt to identify potent and selective DP2 receptor agonists we compared the abilities of a series of PGD2 analogs to activate eosinophils via the DP2 receptor with their abilities to stimulate adenylyl cyclase in platelets via the DP1 receptor. All of the PGD2 analogs tested stimulated CD11b expression and actin polymerization with a rank order of potency of 15R-methyl-PGD2 > PGD2 > 17-phenyl-18,19,20-trinor-PGD2 > 15S-methyl-PGD2 approximately equal16,16-dimethyl-PGD2 > 11-keto-fluprostenol. Surprisingly, 15R-methyl-PGD2, which has the unnatural R-configuration at carbon 15, was about 5 times more potent than PGD2 and about 75 times more potent than 15S-methyl-PGD2. 15R-methyl-PGD2 (EC50 value of 1.7 nM) was also much more potent as an eosinophil chemoattractant than PGD2 (EC50 value of 10 nM) and 15S-methyl-PGD2 (EC50 value of 128 nM). Cross-desensitization experiments indicated that 15R-methyl-PGD2 acts through the DP2 receptor. None of the PGD2 analogs tested elevated platelet cAMP by more than 20% of the maximal level in response to PGD2. However, in contrast to eosinophils, the most active was 15S-methyl-PGD2. In conclusion, 15R-methyl-PGD2 is the most potent known DP2 receptor agonist, and because of its selectivity and resistance to metabolism, should be a useful tool in probing the physiological role of this receptor in inflammatory diseases.     

Behavioral effects of nonbenzodiazepine anxiolytic drugs: a comparison of CGS 9896 and zopiclone with chlordiazepoxide

Zopiclone and CGS 9896 are two nonbenzodiazepine compounds which have been shown to displace benzodiazepines from their binding sites. The present study compared the behavioral effects of these two compounds in rats with those of chlordiazepoxide. The three drugs produced dose-related increases in punished drinking as did pentobarbital and meprobamate but not PK 9084, which also acts at benzodiazepine binding sites, or buspirone. Rates of lever pressing suppressed by punishment were also increased by chlordiazepoxide and zopiclone. CGS 9896 exerted a similar although less marked effect. Lever pressing maintained by a differential reinforcement of low rate 18-sec schedule of milk presentation was increased by low doses of chlordiazepoxide and zopiclone and decreased by higher doses leading to dose-related reductions in numbers of reinforcers obtained. CGS 9896 also reduced number of reinforcers but without affecting rate of responding. In rats trained to discriminate a dose of chlordiazepoxide from saline, chlordiazepoxide, zopiclone, pentobarbital and meprobamate produced chlordiazepoxide-appropriate responding. CGS 9896 also produced chlordiazepoxide-appropriate responding at a wide range of doses although the stimulus properties of this compound appeared to be weaker than those of the other active drugs. Chlordiazepoxide and zopiclone produced dose-related increases in food intake in food-deprived rats. CGS 9896 had similar effects at low doses but its effects were less consistent at higher doses. Thus, zopiclone has a behavioral profile very similar to that of chlordiazepoxide. Although many of the effects of CGS 9896 were similar to those of chlordiazepoxide, a number of differences were also observed.     

PAT5A: a partial agonist of peroxisome proliferator-activated receptor gamma is a potent antidiabetic thiazolidinedione yet weakly adipogenic

PAT5A [5-[4-[N-(2-pyridyl)-(2S)-pyrrolidine-2-methoxyl]phenylmethylene[thiazolidine-2,4-dione, malic acid salt]], a chemically distinct unsaturated thiazolidinedione, activates peroxisome proliferator-activated receptor gamma (PPARgamma) submaximally in vitro with the binding affinity approximately 10 times less than that of rosiglitazone, a highly potent thiazolidinedione. PAT5A reduces plasma glucose level and improves insulin sensitivity in insulin resistant db/db mice, similar to that of rosiglitazone, while exerting a relatively weak adipogenic effect. In contrast to rosiglitazone, PAT5A inhibits cholesterol and fatty acid biosynthesis suggesting that PAT5A possesses a unique receptor-independent non-PPAR related property. PAT5A induces qualitatively similar but quantitatively different protease digestion patterns and interacts with PPARgamma differently than rosiglitazone. PAT5A shows differential cofactor recruitment and gene activation than that of rosiglitazone. Thus, the partial agonism of PAT5A to PPARgamma together with its receptor independent effects may contribute to its antidiabetic potency similar to rosiglitazone in vivo despite reduced affinity for PPARgamma. These biological effects suggest that PAT5A is a PPARgamma modulator that activates some (insulin sensitization), but not all (adipogenesis), PPARgamma-signaling pathways.     

SL65.0155, a novel 5-hydroxytryptamine(4) receptor partial agonist with potent cognition-enhancing properties

SL65.0155 [5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-(2-phenyl ethyl)-4-piperidinyl]-1,3,4-oxadiazol-2(3H)-one monohydrochloride] is a novel benzodioxanoxadiazolone compound with high affinity for human 5-hydroxytryptamine (5-HT)(4) receptors (K(i) of 0.6 nM) and good selectivity (greater than 100-fold for all other receptors tested). In cells expressing the 5-HT(4(b)) and 5-HT(4(e)) splice variants, SL65.0155 acted as a partial agonist, stimulating cAMP production with a maximal effect of 40 to 50% of serotonin. However, in the rat esophagus preparation, SL65.0155 acted as a 5-HT(4) antagonist with a pK(b) of 8.81. In addition, SL65.0155 potently improved performance in several tests of learning and memory. In the object recognition task, it improved retention at 24 h when administered i.p. or p.o. (0.001-0.1 mg/kg). This effect was antagonized by the 5-HT(4) antagonist SDZ 205,557, itself without effect, demonstrating that the promnesic effects of SL65.0155 are mediated by 5-HT(4) agonism. SL65.0155 also reversed the cognitive deficits of aged rats in the linear maze task and the scopolamine-induced deficit of mice in the water maze task. Furthermore, the combined administration of an inactive dose of SL65.0155 with the cholinesterase inhibitor rivastigmine resulted in a significant promnesic effect, suggesting a synergistic interaction. SL65.0155 was devoid of unwanted cardiovascular, gastrointestinal, or central nervous system effects with doses up to more than 100-fold higher than those active in the cognitive tests. These results characterize SL65.0155 as a novel promnesic agent acting via 5-HT(4) receptors, with an excellent preclinical profile. Its broad range of activity in cognitive tests and synergism with cholinesterase inhibitors suggest that SL65.0155 represents a promising new agent for the treatment of dementia.     

Pharmacological activity of the isomers of LY53857, potent and selective 5-HT2 receptor antagonists

LY53857 is an ergoline derivative that is a potent and selective antagonist at 5-HT2 receptors. The present study investigated the activities of the diastereomers of LY53857. The SS- and RR-isomers and the meso mixture of isomers of LY53857 all showed affinity for 5-HT2 receptors approximately 100-fold higher than for 5-HT1 receptors based on radiolabeled ligand binding studies in rat cortical membranes. Based on these binding data, the meso mixture of isomers was one-half as potent as the other two isomers. Consistent with the binding data, the SS- and RR-isomers and the meso mixture of isomers all showed high affinity as antagonists of 5-HT2 receptors in the rat jugular vein, with the meso mixture of isomers being slightly less potent than the other two isomers. Affinity of the isomers at alpha-1 and alpha-2 receptors was low. Approximately 100,000- and 2000-fold higher concentrations were required for antagonism of alpha-1 and alpha-2 receptors, respectively, relative to 5-HT2 receptors. A similar profile of selectivity was demonstrated for each of the isomers studied. These in vitro data were consistent with in vivo data showing the high i.v. and p.o. potency of all the isomers to antagonize the pressor response to i.v. administration of serotonin in pithed spontaneously hypertensive rats. As seen in vitro, the meso mixture of isomers was slightly less potent than the SS- and RR-isomers after p.o. administration in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)