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At least 613 records · Page 34Linked to original sources
PubMed2005

Reversal of isolation-rearing-induced PPI deficits by an alpha7 nicotinic receptor agonist.

RATIONALE: The alpha7 subtype of the nicotinic receptor plays an important role in auditory sensory gating. Schizophrenics show deficient sensory gating and abnormalities in the number and regulation of nicotinic receptors. Prepulse inhibition (PPI) deficits exhibited by isolation-reared rats are thought to model the sensorimotor gating deficits seen in schizophrenia. OBJECTIVE: To examine the role of nicotinic alpha7 receptors in the isolation-rearing rat model, we tested whether the selective alpha7 receptor agonist (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide) (compound A) could reverse isolation-rearing-induced PPI deficits, and investigated alpha7 receptor RNA expression in the hippocampus, prefrontal cortex, cerebellum, nucleus accumbens and thalamus, and alpha7 receptor protein expression in the hippocampus of isolation- and group-reared rats. METHOD: Rats reared in isolation or groups of five from weaning were tested in the PPI paradigm under conditions of variable inter-stimulus interval (ISI) (pulse = 110 dB/50 ms; prepulse = 75 dB/30 ms; ISI = 30, 100 and 300 ms) 30 min following administration of compound A (3.2-10 mg/kg i.p.). Alpha7 receptor expression was measured by TaqMan RT-PCR (total RNA) and autoradiography (protein). RESULTS: Isolation-rearing-induced PPI deficits were attenuated by both doses of compound A at 100-ms ISI and by 10 mg/kg at 300-ms ISI. Expression of alpha7 receptor RNA and protein was unaltered in isolation-reared rats. CONCLUSION: Although altered alpha7 receptor expression may not underlie the phenotype of isolation-reared rats, the activation of these receptors may be of benefit in re-establishing efficient gating function.

Aconitine↗
PubMed2006

Nicotine, but neither the alpha4beta2 ligand RJR2403 nor an alpha7 nAChR subtype selective agonist, protects against a partial 6-hydroxydopamine lesion of the rat median forebrain bundle.

Although previous studies suggest nicotine protects against a 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal tract in rats, it is not known whether functional motor recovery occurs or which nicotinic acetylcholine receptor (nAChR) subtypes mediate this effect. These issues were investigated by comparing the effects of the subtype-specific nAChR agonists, RJR2403 (alpha4beta2 preferring) and (R)-N-(1-azabicyclo[2.2.2.]oct-3-yl)(5-(2-pyridyl)thiopene-2-carboxamide (Compound A; alpha7-selective) and nicotine given 30 min prior to and daily for 14 days after a partial 6-OHDA lesion. In vehicle treated animals, 6-OHDA (6 microg) produced a 65 +/- 1.8% loss of striatal tyrosine hydroxylase (TH) immunoreactivity in the lesion versus intact hemisphere. This loss was reduced in animals treated with nicotine (0.6 and 0.8 mg kg(-1)), reaching significance at the higher dose (36.6 +/- 3.7% loss; P < 0.01 versus vehicle). Treatment with nicotine (0.6 and 0.8 mg kg(-1)) also significantly reduced the number of amphetamine-induced rotations compared to vehicle treatment. In contrast, treatment with RJR2403 (0.2 and 0.4 mg kg(-1)) or Compound A (10 and 20 mg kg(-1)) reduced neither the degree of amphetamine-induced rotations nor the loss of striatal TH immunoreactivity. These data suggest that whilst nicotine is neuroprotective in this partial lesion model, activation of neither the alpha4beta2 nor alpha7 subtypes alone is sufficient to provide protection.

Analysis of Variance↗
PubMed2000

Muscarinic receptor agonists decrease cocaine self-administration rates in drug-naive mice.

(5R,6R)-6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[ 3.2.1]octane (PTAC) is a selective muscarinic receptor ligand. The compound exhibits high affinity for central muscarinic receptors with partial agonist mode of action at muscarinic M(2) and M(4) and antagonist mode of action at muscarinic M(1), M(3) and M(5) receptor subtypes. The compound was earlier reported to exhibit functional dopamine receptor antagonism in rodents despite its lack of affinity for dopamine receptors. In the present study, we report that PTAC, as well as the muscarinic receptor agonists pilocarpine and oxotremorine, dose-dependently decreased rates of intravenous self-administration (fixed ratio 1) of the indirect dopamine receptor agonist cocaine in drug naive mice. Similar decreases in cocaine self-administration rates were obtained with the dopamine receptor antagonists olanzapine, clozapine, risperidone, fluphenazine and haloperidol. These findings suggest that compounds with partial muscarinic receptor agonist mode of action may be used in the medical treatment of cocaine abuse.

Animals↗
PubMed2002

Synthesis and dopamine transporter binding affinities of 3alpha-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes.

A series of 3alpha-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes was synthesized and the binding affinities of the compounds were determined at the dopamine transporter. The unsubstituted analogue 7b (K(i)=98nM) was the most potent compound of the series with binding affinity three-times greater than cocaine and only 5-fold less than GBR-12909. The structure-activity data for 7a-f suggests that these compounds may be binding at the dopamine transporter in a similar fashion to GBR 12909.

Bridged Bicyclo Compounds↗
PubMed2003

Synthesis of dopamine transporter selective 3-[2-(diarylmethoxyethylidene)]-8-alkylaryl-8-azabicyclo[3.2.1]octanes.

A series of 3-[2-(diarylmethoxyethylidene)]-8-alkylaryl-8-azabicyclo[3.2.1]octanes was synthesized and the binding affinities of the compounds were determined at the dopamine and serotonin transporters. The 8-phenylpropyl analogues 8a (K(i)=4.1 nM) and 8b (K(i)=3.7 nM) were the most potent compounds of the series with binding affinities 3 times greater than GBR-12909. In addition, 8a (SERT/DAT=327) was over 300-fold more selective for the dopamine transporter than the serotonin transporter.

Animals↗
PubMed2005

Discovery of the alpha7 nicotinic acetylcholine receptor agonists. (R)-3'-(5-Chlorothiophen-2-yl)spiro-1-azabicyclo[2.2.2]octane-3,5'-[1',3']oxazolidin-2'-one as a novel, potent, selective, and orally bioavailable ligand.

Recent advances in molecular biology suggest that neuronal nicotinic acetylcholine receptors play important roles in the central nervous system (CNS). Of these receptors, the alpha7 group has recently attracted interest for its CNS-related actions and is looked to as a potential new class of pharmacological targets for cognition, schizophrenia, sensory gating, and anxiety. In the course of a research program aimed at the discovery of alpha7 receptor agonists with high affinity, subtype selectivity, and good pharmacokinetic profile, we discovered (R)-3'-(5-chlorothiophen-2-yl)spiro-1-azabicyclo[2.2.2]octane-3,5'-[1',3']oxazolidin-2'-one (25). Compound 25 has potent binding affinity (K(i) = 9 nmol/L) and good selectivity toward the other nicotinic subtypes (alpha4beta2 and alpha1beta2gammadelta) and has been found in pharmacokinetic evaluation to have good oral bioavailability and brain permeability.

Administration, Oral↗
PubMed1994

(-)-Norcocaine.

The title compound, [2R,3S-(2 beta,3 beta)]-methyl 3-(benzoyloxy)-8-azabicyclo[3.2.1]octane-2-carboxylate, C16H19NO4, is a metabolite of the tropane alkaloid cocaine. The molecule crystallized as the free base with the piperidine ring in a chair conformation. The tropane ring system and its methoxycarbonyl and benzoyl groups are rigid; only rotational flexibility is allowed in the conformation of the substituents.

Cocaine↗
PubMed2006

Preclinical and clinical pharmacology of DOV 216,303, a "triple" reuptake inhibitor.

DOV 216,303 [(+/-)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride] is the prototype of a class of compounds referred to as "triple" reuptake inhibitors. Such compounds inhibit the reuptake of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), the three neurotransmitters most closely linked to major depressive disorder. DOV 216,303 inhibits [(3)H]NE, [(3)H]5-HT, and [(3)H]DA uptake to the corresponding human recombinant transporters (expressed in HEK 293 cells) with IC(50) values of approximately 20, 14, and 78 nM, respectively. DOV 216,303 is active in tests predictive of antidepressant activity including the mouse forced swim test and reversal of tetrabenazine-induced ptosis and locomotor depression. The pharmacodynamic, pharmacokinetic, and toxicological profile of DOV 216,303 in animals prompted us to initiate clinical studies. In both single and multiple dose studies using normal volunteers, DOV 216,303 was safe and well-tolerated. Furthermore, both C(max) and AUC values were dose-proportional between 5-150 mg. The plasma concentrations of DOV 216,303 at doses >10 mg were in excess of the IC(50) values for inhibition of biogenic amine reuptake. In a Phase II study designed to explore the safety and tolerability of DOV 216,303 in depressed individuals, patients received either 100 mg DOV 216,303 (50 mg b.i.d.) or 40 mg citalopram (20 mg, b.i.d.) for two weeks. A placebo arm was not employed in this study because several institutional review boards required administration of an active control to severely depressed individuals. Time dependent reductions in HAM-D scores (the primary outcome measure) were observed in both the DOV 216,303 and citalopram groups compared to baseline scores (p < 0.0001). The side effect profile was not remarkably different between treatment arms. These findings provide preliminary evidence of a clinically meaningful antidepressant action with a molecule capable of inhibiting the three transmitters most closely linked to major depressive disorder.

Animals↗
PubMed1996

Potent antitumor activity of quinolone compounds with an unsaturated aminoazabicyclo group at the C-7 position of the quinolone ring.

Relationships between the substituents on the quinolone nucleus of 2 and related compounds and their biological activities were studied. 2, 3 and 1 carrying a (1R, 2R, 6R)-2-amino-8-azabicyclo[4.3.0.]non-3-en-8-yl group at the C-7 position increased the rate of formation of DNA-protein complexes in cells, and inhibited the growth of tumor cells more strongly than the compounds with other substituents. The introduction of a fluorine atom or a methoxy group at the 8-position and an amino group at the 5-position increased the activity still further. The three compounds listed were all effective against P388 leukemia in mice. Subcutaneous injection of 2 at 2 mg/kg strongly suppressed the growth of human MX-1 breast cancer cells in nude mice. 1 has various functional groups that increase the cytotoxic potential of quinolone derivatives: a (1R, 2R, 6R)-2-amino-8-azabicyclo[4.3.0.]non-3-en-8-yl moiety at C-7, a cyclopropyl group at the 1-position, fluorine atoms at the 6- and 8-positions, and an amino group at the 5-position of the quinoline carboxylic acid. These data suggest that this series of compounds provide good models for the further design of potent antitumor quinolones.

Animals↗
PubMed1996

Synthesis of 3 beta-aryl-8-azabicyclo[3.2.1]octanes with high binding affinities and selectivities for the serotonin transporter site.

A novel entry to tropane analogs of cocaine was developed based on the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These analogs were tested in binding to dopamine, serotonin (5-HT), and norepinephrine transporters in membranes from rat striatum and frontal cortex. In all the analogs, the aryl group at the 3 position was directly bound to the tropane ring and an ethyl ketone moiety was present at the 2 position. By appropriate modification of the aryl and nitrogen substituents, highly potent and 5-HT selective tropanes were prepared. The most potent and selective compound was 3 beta-[4-(1-methylethenyl)phenyl]-2 beta-propanoyl-8-azabicyclo[3.2.1]octane (13b) which had a Ki of 0.1 nM at 5-HT transporters and was 150 times more potent at 5-HT vs dopamine transporters and almost 1000 times more potent at 5-HT vs norepinephrine transporters.

Animals↗
PubMed1978

Diastereomeric 7-ureidoacetyl cephalosporins. I. Superiority of 7alpha-H-L-isomers over D-isomers.

The synthesis and in vitro structure-activity relationship of 7-ureidoacetyl cephalosporins carrying various substituents in the 3-position, compounds that showed an enhanced broad spectrum of antibacterial activity, has been outlined. Contrary to most of the previous observations with diastereomeric isomers of cephalosporins, it has been found that the L-side chain isomers also are very potent antibiotics and are even more active inhibitors of certain beta-lactamase-producing Gram-negative bacteria than the corresponding D-side chain isomers. SQ 69,613, 7beta-[[L-[(aminocarbonyl)amino]-2-furanylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl) thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt, the most active compound tested, except for activity against staphylococci, was as active in vitro as cefamandole.

Amino Acids↗
PubMedDate not supplied

Two- and three dimensional combinatorial chemistry from multicomponent Grignard reagents.

The conjugate addition of five component Grignard reagents to methyl ecgonidine was used to create libraries of 3-substituted tropanes. By variation in the reagent combination in 10 such 5-membered sublibraries, a library of 25 compounds was made in a two-dimensional format. Screening of this library led to identification of two new potent monoamine transporter ligands that were subsequently synthesized. The most potent compound in this library was (1R,2S,3S,5S)-3-(3,4-dimethylphenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester, which inhibited dopamine transporter (hDAT) binding and reuptake with a K(i) of 26 and 20 nM, respectively. The conjugate addition to a 5-membered library of methyl ecgonidine analogues with variation of nitrogen substituent was also carried out and used to create 15 sublibraries of 25 compounds, which displayed 125 compounds in a three-dimensional format. From this 3D library, several potent dopamine transport inhibitors were likewise identified and synthesized. The most potent hDAT inhibitor discovered was (1R,2S,3S,5S)-3-(3,4-dimethylphenyl)-8-pentyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester. The study also showed that 3-alkyltropanes were poor inhibitors of monoamine transporters.

Alcohols↗
PubMed1998

Synthesis and 5-HT-3 receptor binding of 2- and 3-(halo)alkoxyl substituted (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chlorobenzamides as potential radioligands.

In an effort to develop selective, high-affinity radioligands for the 5-HT-3 receptor, a series of homologues of 5-chloro-2,3-dimethoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide (2b) was prepared in which individual methoxy groups were replaced by ethoxyl, (2-fluoroethoxyl), allyloxyl, propargyloxyl, or (3-iodoallyl)oxyl groups. Affinities for the 5-HT-3 receptor were determined by displacement of the binding of [125I]MIZAC (2a), a selective 5-HT-3 receptor antagonist radioligand, in rat brain homogenates. The 3-substituted homologues were more potent than the lead compound, 2b. The homologue having the largest 3-substituent, i.e., E-(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-3-(3-iodo-2-propenyl)oxy- 2-methoxybenzamide (3b, THIZAC), had one of the highest affinities, Ki 0.08 nM. The 2-substituted homologues were equipotent with 2b, having Ki 0.2-0.3 nM, regardless of the size of the substituent. The corresponding iodoallyl derivative, E-(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-(3-iodo-2-propenyl)oxy- 3-methoxybenzamide (4, LIZAC), displayed a Ki of 0.29 nM. Saturation binding of [125I]-4 gave a KD of 0.31 +/- 0.04 nM and a Bmax of 2.36 +/- 0.10 fmol/mg of entorhinal cortex. In vivo biodistribution of [125I]-4 in the rat brain showed increased accumulation in hippocampus relative to that in cerebellum. Both the high-affinity ligands [125I]-3b and [125I]-4 are potentially useful radioligands for studying the 5-HT-3 receptor.

Animals↗
PubMed2003

"Broad spectrum" antidepressants: is more better for the treatment of depression?

The majority of antidepressants in current use selectively inhibit the reuptake of serotonin and/or norepinephrine. "Broad spectrum" antidepressants are compounds that inhibit the reuptake of norepinephrine, serotonin and dopamine, the three biogenic amines most closely linked to depression. The pharmacological profile of one such compound has recently been described (European Journal of Pharmacology, 461 (2003) 99). DOV 21,947, an azabicyclo[3.1.0]hexane, potently inhibits norepinephrine, serotonin and dopamine reuptake by the corresponding human transporter proteins. DOV 21,947 is orally active in the forced swim and tail suspension tests, preclinical procedures that are highly predictive of antidepressant action in patients. A closely related compound, DOV 216,303 is safe and well-tolerated in Phase I studies. The plasma concentrations of DOV 216,303 following both single and multiple doses appear sufficient to inhibit norepinephrine, serotonin, and dopamine reuptake. Based on the pivotal role proposed for dopamine in depression, it has been hypothesized that a broad spectrum antidepressant will produce a more rapid onset and/or higher efficacy than agents inhibiting the reuptake of serotonin and/or norepinephrine.

Animals↗
PubMed1991

[Characterization of 9 slowly dissociated opioid ligands azabicyclononances compounds to mu, delta, and kappa receptors].

In the receptor binding assay, the relative affinity ratios of P-7548 [3-(beta-phenylethyl)-9 beta-methoxy-9 alpha-(m-propionoxyphenyl)-3- azabicyclo (3,3,1)nonane], P-7556 [3-(beta-phenylethyl)-9 beta-methoxy-9 alpha-(m-benzoyloxyphenyl)-3- azabicyclo(3,3,1)nonane] and P-7618 [3-(beta-phenylethyl)-9 beta-methoxy-9 alpha-[m-(1-cyclopentyl- propionoxyphenyl)]-3-azabicyclo(3,3,1)nonane] were 56:16:1, 1:4:1, and 6:0.2:1 at mu, delta, and kappa sites, respectively. These compounds possessed a tight binding to mu receptor. After washed 4 times, they still inhibited the [3H]ohmefentanyl binding by 70-80%. In the guinea pig ileum, they showed potent and persistent agonist activities, 607, 303, and 181 times respectively that of normorphine. These effects were readily antagonized by naloxone and Mr2266. In the mouse vas deferens (MVD), they also possessed long-lasting agonist activities. The effect of P-7556 on MVD was not antagonized by naloxone and Mr2266, indicating that P-7556 acted on delta receptor in MVD. In the rabbit vas deferens, P-7548, P-7556, and P-7618 antagonized the effect of U-50488H. We conclude that these azabicyclononanes are a series of opioid ligands with mu, delta agonist and kappa antagonist activities.

Analgesics↗
PubMed2003

Synthesis of enantiopure 3-azabicyclo[3.2.0]heptanes by diastereoselective intramolecular [2+2] photocycloaddition reactions on chiral perhydro-1,3-benzoxazines.

[2+2] photocycloadditions involving chiral 3-acryloyl-2-vinylperhydro-1,3-benzoxazines derived from (-)-8-aminomenthol are highly diastereoselective reactions. The facial selectivity depends on the type of substitution at the vinyl double bond, and always leads to cis-fused bicyclic derivatives. The de is good for compounds with one substituent at the outer carbon of the double bond at C-2, but only one diastereomer is formed in cyclizations of compounds with two substituents at that position. The elimination of the menthol appendage gives enantiopure 3-azabicyclo[3.2.0]heptanes.

Journal Article↗
PubMed2000

Synthesis of enantiopure 3-quinuclidinone analogues with three stereogenic centers: (1S,2R,4S)- and (1S,2S, 4S)-2-(Hydroxymethyl)-1-azabicyclo[2.2.2]octan-5-one and stereocontrol of nucleophilic addition to the carbonyl group.

The pseudoenantiomeric title compounds have been prepared from quincorine (QCI) and quincoridine (QCD), respectively, in enantiopure form following an efficient six-step pathway. Nucleophilic attack at the carbonyl group proceeds preferentially from the supposedly more hindered endo pi-face, giving quinuclidinols with natural configuration at C5 (up to 97%). pi-Face selectivity is highest in the QCD series with bulky O-protecting groups, involving an unprecedented 1,7-stereoinduction.

Indicators and Reagents↗