Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor

We investigated the effects of a novel melanocortin-4 (MC4) receptor antagonist,1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine (MCL0129) on anxiety and depression in various rodent models. MCL0129 inhibited [(125)I][Nle(4)-D-Phe(7)]-alpha-melanocyte-stimulating hormone (alpha-MSH) binding to MC4 receptor with a K(i) value of 7.9 nM, without showing affinity for MC1 and MC3 receptors. MCL0129 at 1 microM had no apparent affinity for other receptors, transporters, and ion channels related to anxiety and depression except for a moderate affinity for the sigma(1) receptor, serotonin transporter, and alpha(1)-adrenoceptor, which means that MCL0129 is selective for the MC4 receptor. MCL0129 attenuated the alpha-MSH-increased cAMP formation in COS-1 cells expressing the MC4 receptor, whereas MCL0129 did not affect basal cAMP levels, thereby indicating that MCL0129 acts as an antagonist at the MC4 receptor. Swim stress markedly induced anxiogenic-like effects in both the light/dark exploration task in mice and the elevated plus-maze task in rats, and MCL0129 reversed the stress-induced anxiogenic-like effects. Under nonstress conditions, MCL0129 prolonged time spent in the light area in the light/dark exploration task and suppressed marble-burying behavior. MCL0129 shortened immobility time in the forced swim test and reduced the number of escape failures in inescapable shocks in the learned helplessness test, thus indicating an antidepressant potential. In contrast, MCL0129 had negligible effects on spontaneous locomotor activity, Rotarod performance, and hexobarbital-induced anesthesia. These observations indicate that MCL0129 is a potent and selective MC4 antagonist with anxiolytic- and antidepressant-like activities in various rodent models. MC4 receptor antagonists may prove effective for treating subjects with stress-related disorders such as depression and/or anxiety.     

Physico-chemical properties of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) diazonium ion: a theoretical investigation

We have explored the physico-chemical properties of NNK diazonium ion to gain insight into its shape, bonding, charge distribution, and ro-vibrational features. This information is essential if the chemical reactivity and physical properties of this important intermediate are to be understood. NNK diazonium ion is a well-known alkylating agent. Its enzymatic production, its reaction with DNA, and its role in mutagenesis/carcinogenesis have all received significant experimental study. Computational work on the ion, however, is lacking. The species is sufficiently small such that its properties may be probed using sophisticated model chemistries. We present the first in silico investigation of NNK diazonium ion. Kohn–Sham density functional theory (B3LYP/6-311G**) and coupled cluster theory (CCSD/6-31G*) were deployed to obtain energies, geometries, electrostatic potential surfaces, molecular orbitals, and vibrational analyses for several energy-minimized structures. To provide insight into the motion of NNK diazonium ion (NNKDI) in solution, molecular dynamics simulations on the solvated intermediate were undertaken. To explore the initial reactivity of this important electrophile, local Fukui indices and natural population analysis charges were predicted. Analogous ab initio work on propane diazonium ion was also performed. Our vibrational analyses suggest a relatively weak carbon–nitrogen bond and a robust nitrogen–nitrogen interaction. Our condensed Fukui indices show that the terminal nitrogen is a site of significant electrophilicity while our electrostatic predictions yield high values near the formally charged nitrogen and its α carbon.

NNKDI TCTT molecular orbital energies (a), molecular orbitals 46 (HOMO), 47 (LUMO) and 48 (LUMO+1) as calculated at the B3LYP/6-311G** level of theory.     

Nephrotoxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) in the Fischer 344 rat

A single s.c. injection of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU; 20-140 mg/kg) resulted in rapid decreases in renal function as well as leading to a chronic progressive nephropathy in male Fischer 344 rats. Disturbances in renal function were proportional to the dose of MeCCNU administered and included impaired tubular transport of p-aminohippuric acid, a decrease in urine concentrating ability, an increase in urine pH, polyuria, proteinuria and enzymuria. The tubular accumulation of p-aminohippuric acid by kidney slices was decreased as early as 1 hr after MeCCNU administration (100 mg/kg), was maximal within 12 hr and remained depressed for at least 28 days after a single injection of either 40 or 80 mg/kg. Changes in other measures of renal function (increased lactate dehydrogenase excretion, alkalinuria and decreased urine concentrating ability) were delayed from 1 to 6 days after MeCCNU administration and in some cases progressed in severity throughout the 28-day duration of the experiment. The delay between the first evidence of renal damage (decreased p-aminohippuric acid uptake) and the subsequent appearance of enzymuria, proteinuria, polyuria and alkalinuria appears to correspond to a similar delay between the initial insult and the eventual development of cellular necrosis and other histopathological changes. These results demonstrate that MeCCNU is a nephrotoxicant in rats and indicate that even a single acute dose may lead to chronic and irreversible effects on the kidney. The in vivo toxicity model defined herein appears to be an appropriate one for further study of the mechanism of nephrotoxicity of MeCCNU.     

Effects of buthionine sulfoximine on the nephrotoxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU)

Administration of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1 1-nitrosourea (MeCCNU; 50-500 mg/kg) to male F344 rats caused a time- and dose-related decrease of glutathione (GSH) preferentially in the liver, but not in the kidney. A 500-mg/kg dose of MeCCNU decreased liver, lung and kidney GSH by 69, 15 and 3%, respectively, 2 hr after dosing. However, MeCCNU had no effect on the ratio of GSH/oxidized GSH or on GSH reductase activity in any tissue tested. A single i.p. dose of DL-buthionine-SR-sulfoximine, an inhibitor of GSH biosynthesis, caused tissue GSH levels to decrease at a rate which reflected the biological half-life of GSH in the respective organs. The T 1/2 for GSH in kidney, liver and lung was found to be 1.5, 5 and 9 hr, respectively. MeCCNU administered s.c. to DL-buthionine-SR-sulfoximine-pretreated rats resulted in a depletion of hepatic and renal GSH concentrations which was additive to the effects of either of these treatments alone. DL-Buthionine-SR-sulfoximine also markedly increased the nephrotoxicity of MeCCNU and resulted in a hepatotoxicity not ordinarily seen when MeCCNU was administered alone. These results suggest that a reactive electrophilic intermediate may be involved in the mechanism of MeCCNU nephrotoxicity. Moreover, that renal GSH may play a protective role against MeCCNU-induced nephrotoxicity.     

Inhibition of improgan antinociception by the cannabinoid (CB)(1) antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A): lack of obligatory role for endocannabinoids acting at CB(1) receptors

Improgan, a nonopioid antinociceptive agent, activates descending, pain-relieving mechanisms in the brain stem, but the receptor for this compound has not been identified. Because cannabinoids also activate nonopioid analgesia by a brain stem action, experiments were performed to assess the significance of cannabinoid mechanisms in improgan antinociception. The cannabinoid CB(1) antagonist N-(piperidin-1-yl)-5-(4-chloro phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) induced dose-dependent inhibition of improgan antinociception on the tail-flick test after i.c.v. administration in rats. The same treatments yielded comparable inhibition of cannabinoid [R-(+)-(2,3-dihydro-5-methyl-3-[(4-mor pholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl)methanone monomethanesulfonate, WIN 55,212-2] analgesia. Inhibition of improgan and WIN 55,212-2 antinociception by SR141716A was also observed in Swiss-Webster mice. Radioligand binding studies showed no appreciable affinity of improgan on rat brain, mouse brain, and human recombinant CB(1) receptors, ruling out a direct action at these sites. To test the hypothesis that CB(1) receptors indirectly participate in improgan signaling, the effects of improgan were assessed in mice with a null mutation of the CB(1) gene with and without SR141716A pretreatment. Surprisingly, improgan induced complete antinociception in both CB(1) (-/-) and wild-type control [CB(1) (+/+)] mice. Furthermore, SR141716A inhibited improgan antinociception in CB(1) (+/+) mice, but not in CB(1) (-/-) mice. Taken together, the results show that SR141716A reduces improgan antinociception, but neither cannabinoids nor CB(1) receptors seem to play an obligatory role in improgan signaling. Present and previous studies suggest that Delta(9)-tetrahydrocannabinol may act at both CB(1) and other receptors to relieve pain, but no evidence was found indicating that improgan uses either of these mechanisms. SR141716A will facilitate the study of improgan-like analgesics.     

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. Ro 63-1908 selectively blocked recombinant receptors expressed in Xenopus oocytes containing NR1C + NR2B subunits with an IC(50) of 0.003 microM and those containing NR1C + NR2A subunits with an IC(50) of >100 microM, thus demonstrating greater than 20,000-fold selectivity for the recombinant receptors expressing NR1C + NR2B. Ro 63-1908 blocked these NMDA NR2B-subtype receptors in an activity-dependent manner. Ro 63-1908 was neuroprotective against glutamate-induced toxicity and against oxygen/glucose deprivation-induced toxicity in vitro with IC(50) values of 0.68 and 0.06 microM, respectively. Thus, the in vitro pharmacological characterization demonstrated that Ro 63-1908 was a potent and highly selective antagonist of the NR2B subtype of NMDA receptors. Ro 63-1908 was active against sound-induced seizures (ED(50) = 4.5 mg/kg i.p. when administered 30 min beforehand) in DBA/2 mice. The dose required to give a full anticonvulsant effect did not produce a deficit in the Rotarod test. NMDA-induced seizures were also inhibited by Ro 63-1908 with an ED(50) of 2.31 mg/kg i.v. when administered 15 min before testing. Ro 63-1908 gave a dose-related neuroprotective effect against cortical damage in a model of permanent focal ischemia. Maximum protection of 39% was seen at a plasma concentration of 450 ng/ml. There were, however, no adverse cardiovascular or CNS side-effects seen at this dosing level.     

DuP 734 [1-(cyclopropylmethyl)-4-(2'(4'-fluorophenyl)-2'- oxoethyl)piperidine HBr], a potential antipsychotic agent: preclinical behavioral effects.

It has been suggested that sigma receptors may be involved in the etiology of psychosis and that 5-hydroxytryptamine2 (5-HT2) antagonists may have utility in treating the negative symptoms of psychosis as well as reducing the side effects associated with the typical antipsychotic haloperidol. We have evaluated the potential antipsychotic effects of 1-(cyclopropylmethyl)-4-(2'(4'-fluorophenyl)-2'-oxoethyl)piper i din e HBr (DuP 734), a selective and potent sigma and 5-HT2 receptor ligand with weak affinity for D2 receptors, in behavioral animal models that are not necessarily dependent on dopamine antagonism. DuP 734 potently blocked mescaline-induced scratching (ED50 = 0.35 mg/kg, p.o.) and aggressive activity (ED50 = 1.9 mg/kg, p.o.) and was relatively much weaker as an apomorphine antagonist (ED50 = 12 mg/kg, p.o.). This was in contrast to the typical antipsychotic agents such as haloperidol and chlorpromazine, which were very potent in all three tests. In rats, DuP 734 did not antagonize avoidance behavior or induce catalepsy, and, therefore, differed from the potent dopamine receptor antagonist antipsychotics. It did, however, reduce lever response rates in a random interval 60-sec food reward schedule of reinforcement (ED50 = 6.0 mg/kg, p.o.) in rats. The results suggest that DuP 734 may have antipsychotic activity without the liability of motor side effects typical of neuroleptics. Although DuP 734 itself did not antagonize avoidance activity, it significantly enhanced the potency of haloperidol in blocking avoidance behavior by 3-fold (by shifting the ED50 from 0.94 to 0.36 mg/kg, p.o.), whereas the ED50 of haloperidol for blockade of escape behavior and induction of catalepsy was not affected.(ABSTRACT TRUNCATED AT 250 WORDS)     

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A): a potent and selective corticotrophin-releasing factor(1) receptor antagonist. I. Biochemical and pharmacological characterization

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1- (3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A), a new 2-aminothiazole derivative, shows nanomolar affinity for human cloned or native corticotrophin-releasing factor (CRF)(1) receptors (pK(i) values of 8.73 and 9.08, respectively), and a 1000-fold selectivity for CRF(1) versus CRF(2 alpha) receptor and CRF binding protein. SSR125543A antagonizes CRF-induced stimulation of cAMP synthesis in human retinoblastoma Y 79 cells (IC(50) = 3.0 +/- 0.4 nM) and adrenocorticotropin hormone (ACTH) secretion in mouse pituitary tumor AtT-20 cells. SSR125543A is devoid of agonist activity in these models. Its brain penetration was demonstrated in rats by using an ex vivo [(125)I-Tyr(0)] ovine CRF binding assay. SSR125543A displaced radioligand binding to the CRF(1) receptor in the brain with an ID(50) of 6.5 mg/kg p.o. (duration of action >24 h). SSR125543A also inhibited the increase in plasma ACTH levels elicited in rats by i.v. CRF (4 microg/kg) injection (ID(50) = 1, 5, or 5 mg/kg i.v., i.p., and p.o., respectively); this effect lasted for more than 6 h when the drug was given orally at a dose of 30 mg/kg. SSR125543A (10 mg/kg p.o.) reduced by 73% the increase in plasma ACTH levels elicited by a 15-min restraint stress in rats. Moreover, SSR125543A (20 mg/kg i.p.) also antagonized the increase of hippocampal acetylcholine release induced by i.c.v. injection of 1 microg of CRF in rats. Finally, SSR125543A reduced forepaw treading induced by i.c.v. injection of 1 microg of CRF in gerbils (ID(50) = approximately 10 mg/kg p.o.). Altogether, these data indicate that SSR125543A is a potent, selective, and orally active CRF(1) receptor antagonist.     

Pharmacological profile of (2R-trans)-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-Hydroxybutanedioate (R116301), an orally and centrally active neurokinin-1 receptor antagonist

In comparison with a series of reference compounds, (2R-trans)-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-Hydroxybutanedioate (R116301) was characterized as a specific, orally, and centrally active neurokinin-1 (NK(1)) receptor antagonist with subnanomolar affinity for the human NK(1) receptor (K(i): 0.45 nM) and over 200-fold selectivity toward NK(2) and NK(3) receptors. R116301 inhibited substance P (SP)-induced peripheral effects (skin reactions and plasma extravasation in guinea pigs) and a central effect (thumping in gerbils) at low doses (0.08-0.16 mg/kg, s.c. or i.p.), reflecting its high potency as an NK(1) receptor antagonist and excellent brain disposition. Higher doses blocked various emetic stimuli in ferrets, cats, and dogs (ED(50) values: 3.2 mg/kg, s.c.; 0.72-2.5 mg/kg, p.o.). Even higher doses (11-25 mg/kg, s.c.) were required in mice (capsaicin-induced ear edema) and rats (SP-induced extravasation and salivation), consistent with lower affinity for the rodent NK(1) receptor and known species differences in NK(1) receptor interactions. R116301 inhibited the ocular discharge (0.034 mg/kg) but not the dyspnoea, lethality, or cough (>40 mg/kg, s.c.) induced by [betaALA(8)]-neurokinin A (NKA) (4-10) in guinea pigs, attesting to NK(1) over NK(2) selectivity. R116301 did not affect senktide-induced miosis (>5 mg/kg, s.c.) in rabbits, confirming the absence of an interaction with the NK(3) receptor. R116301 was inactive in guinea pigs against skin reactions induced by histamine, platelet-aggregating factor, bradykinin, or Ascaris allergens (>10 mg/kg, s.c.). In all species, R116301 showed excellent oral over parenteral activity (ratio, 0.22-2.7) and a relatively long duration (6.5-16 h, p.o.). The data attest to the specificity and sensitivity of the animal models and support a role of NK(1) receptors in various diseases.     

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1, 3-thiazol-2-amine hydrochloride (SSR125543A), a potent and selective corticotrophin-releasing factor(1) receptor antagonist. II. Characterization in rodent models of stress-related disorders

The present study investigated the effects of the novel corticotrophin-releasing factor (CRF)(1) receptor antagonist 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A) in a variety of rodent models of anxiety, including conflict procedures (punished drinking and four-plate), exploration models (elevated plus-maze and light/dark), a fear/anxiety defense test battery, and several procedures based on stress-induced changes in physiological (isolation-induced hyperthermia and tail pinch-induced cortical norepinephrine release) or behavioral (social defeat-induced anxiety, maternal separation-induced vocalization) parameters. Moreover, the effects of SSR125543A were investigated in acute (forced swimming) and chronic (chronic mild stress; CMS) models of depression. SSR125543A and the CRF(1) receptor antagonist antalarmin displayed limited efficacy in exploration-based anxiety models. In contrast, both compounds produced clear-cut anxiolytic-like activity in models involving inescapable stress, including the conflict procedures, the social defeat-induced anxiety paradigm and the defense test battery (3-30 mg/kg i.p. or p.o.). These effects paralleled those of the anxiolytic diazepam. In addition, SSR125543A and antalarmin antagonized stress-induced hyperthermia, distress vocalization, and cortical norepinephrine release. In the forced swimming test, 30 mg/kg p.o. SSR125543A and 3 to 30 mg/kg p.o. antalarmin produced clear antidepressant-like effects. These latter results were strengthened by the findings from the CMS, which showed that repeated administration of 10 mg/kg i.p. SSR125543A for 30 days improved the degradation of the physical state, the reduction of body weight gain, and anxiety produced by stress. Together, these data indicate that SSR125543A shows good activity in acute and chronic tests of unavoidable stress exposure, suggesting that it may have a potential in the treatment of depression and some forms of anxiety disorders.     

The benzamide derivative N-[1-(7-tert-Butyl-1H-indol-3-ylmethyl)-2-(4-cyclopropanecarbonyl-3-methyl-piperazin-1-yl)-2-oxo-ethyl]-4-nitro-benzamide (SP-10) reduces HIV-1 infectivity in vitro by modifying actin dynamics

Current treatments for patients infected with HIV are suboptimal. There is a need for new HIV therapies that act through different mechanisms than current treatments. We investigated the in vitro efficacy, safety and mechanism of action of the benzamide derivative N-[1-(7-tert-Butyl-1H-indol-3-ylmethyl)-2-(4-cyclopropanecarbonyl-3-methyl-piperazin-1-yl)-2-oxo-ethyl]-4-nitro-benzamide (SP-10), a potential new HIV treatment. When HIV-1-responsive engineered HeLa cells were pre-incubated for 48 h with either SP-10 or zidovudine (AZT), SP-10 was able to inhibit viral replication at much lower concentrations (IC50 = 0.036 nM) than AZT (IC50 = 27.4 nM). In contrast to AZT, SP-10 also inhibited replication of the multidrug-resistant HIV-1 strain MDR-769 in the HeLa cell model. In co-incubation experiments, SP-10 also inhibited the CCR5-sensitive HIV-1 BaL virus replication in human peripheral blood mononuclear cells. SP-10 displayed very low toxicity compared with current antiviral treatments. Confocal laser scanning microscopy and immunoprecipitation studies showed that SP-10 reduced the expression of CD4 and CCR5 on the surface of the host cell. SP-10 also reduced the level of gp120 binding to the cell surface. Confocal laser scanning microscopy studies showed that SP-10 blocked the formation of actin filaments (F-actin) and altered actin accumulation near the cell surface. These promising results suggest that SP-10 has a novel mechanism of action that enables effective inhibition of HIV-1 binding and cell entry. Further development of SP-10 as a new HIV treatment appears warranted.     

SR147778 [5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide], a new potent and selective antagonist of the CB1 cannabinoid receptor: biochemical and pharmacological characterization

Based on binding, functional, and pharmacological data, this study introduces SR147778 [5-(4-bromophenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide] as a highly potent, selective, and orally active antagonist for the CB1 receptor. This compound displays nanomolar affinity (Ki = 0.56 and 3.5 nM) for both the rat brain and human CB1 recombinant receptors, respectively. It has low affinity (Ki = 400 nM) for both the rat spleen and human CB2 receptors. Furthermore, it shows no affinity for any of the over 100 targets investigated (IC50 > 1 microM). In vitro, SR147778 antagonizes the inhibitory effects of CP 55,940 [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol] on both the mouse vas deferens contractions (pA2 value = 8.1) and on forskolin-stimulated adenylyl cyclase activity in the U373 MG cell lines (pA2 value = 8.2) but not in Chinese hamster ovary (CHO) cells permanently expressing the human peripheral cannabinoid receptor (hCB2). SR147778 is able to block the mitogen-activated protein kinase activity induced by CP 55,940 in the CHO cell line expressing human brain cannabinoid receptor (IC50 = 9.6 nM) but was inactive in cells expressing hCB2. After oral administration, SR147778 displaced the ex vivo [3H]-CP 55,940 binding to mouse brain membranes (ED50 = 3.8 mg/kg) with a long duration of action, whereas it did not interact with the CB2 receptor expressed in the mouse spleen. Using different routes of administration, SR147778 (0.3-3 mg/kg) is shown to antagonize pharmacological effects (hypothermia, analgesia, and gastrointestinal transit) induced by R-(+)-(2,3-dihydro-5-methyl-3-[[4-morpholinyl]methyl] pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone in mice. Finally, per se, SR147778 (0.3-10 mg/kg) is able to reduce ethanol or sucrose consumption in mice and rats and food intake in fasted and nondeprived rats.     

Imaging Sigma-1 Receptor (S1R) Expression Using Iodine-124-Labeled 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine ([124I]IPAG)

Molecular Imaging and Biology - Sigma-1 receptors (S1Rs) are overexpressed in almost all human cancers, especially in breast cancers. 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine (IPAG) is a validated...     

Effects of two novel D3-selective compounds, NGB 2904 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide] and CJB 090 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide], on the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys

The present study examined the effects of two novel dopamine D3 receptor compounds, NGB 2904 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide], an antagonist, and CJB 090 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide], a partial agonist, in two models of cocaine abuse in rhesus monkeys. To establish a dose range and time course of effects, both compounds were shown to block quinpirole-induced yawning when administered i.m. 15, 30, or 120 min before quinpirole. Next, rhesus monkeys were trained to discriminate i.m. injections of saline (0.5 ml) and cocaine (0.3 mg/kg). Neither D3 compound (0.03-3.0 mg/kg; n=3) substituted for cocaine in any monkey. When given in combination with cocaine, CJB 090 but not NGB 2904 attenuated the discriminative stimulus effects of cocaine, shifting the cocaine dose-response curve to the right. In a separate group of monkeys, responding was maintained under a second-order schedule of either food (1.0-g pellets; n=3) or cocaine (0.1 mg/kg/injection; n=4) presentation. When responding was stable, a dose of NGB 2904 (1.0-5.6 mg/kg i.v.) or CJB 090 (0.3-3.0 mg/kg i.v.) was administered for 5 consecutive days, immediately before the session. CJB 090, but not NGB 2904, decreased cocaine- and food-maintained responding. These data indicate that compounds with relatively high affinity and selectivity for the D3 receptor can attenuate the discriminative and reinforcing stimulus effects of cocaine while not producing cocaine-like effects. The present findings support the continued examination of D3 compounds as pharmacological tools for better understanding the role of this receptor subtype in cocaine addiction and as potential lead compounds for novel therapeutic agents.     

CI-926 (3-[4-[4-(3-methylphenyl)-1-piperazinyl]butyl]-2,4-imidazolinedione): antihypertensive profile and pharmacology

CI-926 (10(-7)-10(-6) M) selectively antagonized the contraction of isolated rabbit aortae to phenylephrine and displaced the alpha-1 adrenoceptor ligand WB4101 (IC50: 82 nM) in rat brain. In the spontaneously hypertensive rat, single oral doses of either CI-926 (0.3-10 mg/kg) or prazosin (0.3-100 mg/kg) caused dose-related reductions in blood pressure; however, CI-926 was more efficacious. The maximal antihypertensive response to CI-926 was unchanged with three consecutive days of oral dosing in the spontaneously hypertensive rat, whereas a first dose effect was noted with prazosin. In two-kidney, one-clip, renal hypertensive rats, CI-926 and prazosin (1-10 mg/kg) lowered blood pressure; however, prazosin was more efficacious. In perinephritic hypertensive dogs, CI-926 (10 mg/kg) lowered blood pressure 20%. In anesthetized dogs, CI-926 in the presence of supermaximal blood pressure-lowering doses of prazosin caused an additional reduction in pressure. With equivalent alpha-1 blockade in anesthetized rats, CI-926 tended to have greater hypotensive activity than prazosin. These results demonstrate that CI-926 is a potent, orally active antihypertensive agent in renin-dependent and -independent hypertension. The profile of CI-926 suggests that it lowers blood pressure in part by interacting with peripheral alpha-1 adrenoceptors and in part via an additional mechanism(s). Although weak relative to its affinity for alpha-1 adrenoceptors, CI-926 was found in preliminary experiments to interact with alpha-2 adrenoceptors, serotonergic receptors and dopaminergic receptors. The importance of these interactions to the blood pressure response of CI-926 remains to be elucidated.