PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Azabicyclo Compounds”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 667 records · Page 37Linked to original sources
PubMed2001

exo-2-(Pyridazin-4-yl)-7-azabicyclo[2.2.1]heptanes: syntheses and nicotinic acetylcholine receptor agonist activity of potent pyridazine analogues of (+/-)-epibatidine.

A new strategy for the straightforward synthesis of novel racemic epibatidine analogues is presented, in which the 2-chloropyridinyl moiety of epibatidine is bioisosterically replaced by differently substituted pyridazine rings. A key step of the new syntheses is the inverse type Diels-Alder reaction of the electron-rich enol ether 13 with the electron-deficient diazadiene systems of the 1,2,4, 5-tetrazines 14a-d to yield the novel pyridazine analogues of (+/-)-epibatidine 18, 19, 22, and 24. In addition preparation of the N-substituted derivatives, such as 26 and 28, is described. The structures of the novel epibatidine analogues were assigned on the basis of spectral data, that of compound 24 being additionally verified by X-ray crystallography exhibiting two racemic solid-state conformations in the crystal lattice and representing the first X-ray structure of an unprotected 7-azabicyclo[2.2.1]heptane moiety. The nAChR agonist activity of the racemic compounds 18, 19, 22, 24, and 28 was assayed in vitro by whole-cell current recordings from Xenopus oocytes expressing different recombinant nicotinic receptors from the rat. Among the compounds synthesized and tested, the pyridazine analogue 24 of (+/-)-epibatidine and its N-methyl derivative 28 were found to be the most active ones retaining much of the potency of natural epibatidine but with a substantially improved selectivity ratio between the alpha4beta2 and alpha3beta4 subtypes.

Animals↗
PubMed1990

Synthesis and muscarinic activities of 1,2,4-thiadiazoles.

A series of novel 1,2,4-thiadiazoles bearing a mono- or bicyclic amine at C5 were prepared. Quinuclidine and 1-azabicyclo[2.2.1]heptane derivatives were synthesized by reaction of the lithium enolate of the 3-methoxycarbonyl compounds followed by ester hydrolysis and decarboxylation. The receptor-binding affinity and efficacy of these compounds as muscarinic ligands was assessed by radioligand binding assays using [3H]-N-methylscopolamine and [3H]oxotremorine-M. Optimal agonist affinity was observed for 3'-methyl compounds. Smaller substituents (H) retained efficacy with reduced affinity while larger groups led to substantially lower efficacy. The observed binding affinity was influenced both by the conformational energy of rotation around the C3-C5' bond and the steric requirement of the mono- or bicyclic amine.

Animals↗
PubMed1978

Synthesis and analgetic activity of some 5-aryl-2azabicyclo[3.2.1]octanes.

A series of 5-aryl-2-azabicyclo[3.2.1]octanes II has been synthesized and evaluated for analgetic agonist-antagonist activity. These compounds can be regarded as five-membered, conformationally more rigid analogues of the potent agonist-antagonist (-)-5-(3-hydroxyphenyl)-2-methylmorphan (I). Several of these compounds have demonstrated marked analgesic potency comparable to morphine in the mouse writhing assay. Structure-activity correlations, generated by varying N-substitution and O-acetylation of the phenolic function, seem to indicate that optimum activity is associated with an arylethyl side chain attached to the basic nitrogen. Among the most interesting compounds in this series are the phenethyl analogue 31 and its O-acetate 39; the former shows the profile of a well-balanced analgetic-antagonist virtually devoid of physical dependence liability as demonstrated in the rat infusion test.

Analgesics↗
PubMed2002

Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2-exo-2-(2',3'-disubstituted 5'-pyridinyl)-7-azabicyclo[2.2.1]heptanes: epibatidine analogues.

A number of 2',3'-disubstituted epibatidine analogues were synthesized and evaluated in vitro for potency at nicotinic acetylcholine receptors (nAChRs) and in vivo for antinociception activity in the tail-flick and hot-plate models of acute pain and for their ability to affect core body temperature. Compounds that possessed electron-withdrawing groups (F, Cl, Br, and I) in both the 2'- and the 3'-positions showed affinities at the nAChR similar to epibatidine. However, in vivo efficacy did not correlate with affinity. 2-exo-(3'-Amino-2'-chloro-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane (2i), an epibatidine analogue possessing an electron-releasing amino group in the 3'-position, produced the highest affinity. Compound 2i was also the most selective epibatidine analogue with a K(i) of 0.001 nM at alphabeta nAChRs, which is 26 times greater than that of epibatidine, and a alphabeta/alpha(7) K(i) ratio of 14,000, twice that of epibatidine. In vivo testing revealed that this compound potently inhibited nicotine-induced antinociception with AD(50) values below 1 microg/kg. Surprisingly, this same compound was also an agonist at higher doses (ED(50) approximately 20 microg/kg). Thus, the addition of the 3'-amino group to epibatidine confers potent antagonist activity to the compound with little effect on agonist activity. 2,3-Disubstituted epibatidine analogues possessing a 2'-amino group combined with a 3'-bromo or 3'-iodo group showed in vitro and in vivo nAChR properties similar to nicotine.

Analgesics, Non-Narcotic↗
PubMed2000

Structural aspects of high affinity ligands for the alpha 4 beta 2 neuronal nicotinic receptor.

Neuronal nicotinic acetylcholine receptors (nAChRs) are a heterogeneous family of related ion channels that are widely distributed throughout the central and peripheral nervous systems. They all share a common architecture of five subunit proteins that combine at the cell surface to create a ligand-gated cation permeable pore. Significant effort is currently being expended by medicinal chemistry teams to synthesize ligands that exhibit selectivity for central over peripheral nAChR subtypes. Within the CNS, multiple nAChR subtypes are recognized, and the discovery of ligands exhibiting selectivity among these subtypes offers an opportunity for the development of novel therapeutic agents. The alpha 4 beta 2 subtype is one of the most abundant nAChR subtypes within the CNS, and has been the primary focus of high affinity ligand design. Nicotine (1), and more recently, epibatidine (2) have served as structural templates for the design of the majority of active compounds. Although the diversity of nAChR ligands is growing, the structural requirements necessary for high affinity binding with the alpha 4 beta 2 receptor remain poorly understood. The putative pharmacophoric elements common to all potent alpha 4 beta 2 ligands include (1) a basic or quaternized nitrogen atom, and (2) a less basic nitrogen or a carbonyl oxygen that presumably interact with electron rich and electron deficient sites on the receptor, respectively. The family of currently known high affinity analogs consists of a diverse array of azacycles containing a basic amine. Several additional basic amine fragments have been identified, including the pyrrolizidine nucleus (exemplified by 8) and the 2-azabicyclo[2.2.1]heptane skeleton (exemplified by 9). In addition, we have found that the furo[2,3-b]pyridine heterocycle (compound 10) serves as useful bioisosteric replacement for the pyridyl substituent of nicotine. A preliminary pharmacophore model is proposed in which a reasonable superposition of the putative pharmacophoric elements of the diverse array of high affinity ligands for the alpha 4 beta 2 nAChR reported herein may be accommodated.

Animals↗
PubMed1986

Dosage regimen design for pharmaceutical studies conducted in animals.

The selection of dosage regimens for different animal species requires the establishment of pharmacokinetic equivalency between species. Pharmacokinetic equivalency can be defined in terms of the magnitude of exposure (i.e., an identical peak serum concentration in each species) and the duration of exposure (i.e., an identical area under the serum concentration-time curve in a finite dosing interval). Using ceftizoxime [(6R,7R)-7-[2-(2-imino-4-thiazolin-4-yl)glyoxylamido]- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 7(2)-(Z)-(O-methyl-oxime)] as a model compound, pharmacokinetic equivalency in mice, rats, monkeys, dogs, and humans was established by selecting a dose for each species that produced similar peak serum concentrations, and by selecting a dosage schedule for each species that produced an equivalent area under the serum concentration-time curve in a 24-h dosing interval. The relationships of animal weight to dose and animal weight to dosing schedule were well described by the power equation Y = aWb, where Y is the dosage variable, W is animal weight, log a is the y-intercept, and b is the slope obtained from the plot of log Y versus log W. Toxicology data for 14 antineoplastic agents were obtained from the literature. The power equation adequately described the relationship between toxic dose and animal weight for most of the compounds, demonstrating the utility of the power equation in the assessment of dosing regimens for toxicity studies as well.

Animals↗
PubMed1989

Structure elucidation of ficellomycin.

The structure of ficellomycin, an antibiotic previously discovered by Argoudelis et al., is elucidated as valyl-2-[4-guanidyl-1-azabicyclo[3.1.0]hexan-2-yl]glycine (1) by NMR, MS, and derivatization studies. The 1-azabicyclo[3.1.0]hexane moiety in 1 represents an unusual ring system making ficellomycin a unique natural product compound.

Anti-Bacterial Agents↗
PubMed1999

The effects of benzamide analogues on cocaine self-administration in rhesus monkeys.

RATIONALE: Based on the differential distribution of dopamine (DA) D(3) receptors in mesolimbic regions relative to nigrostriatal regions, the hypothesis was that D(3)-selective antagonists (i.e., higher affinity at D(3)- than D(2)-receptors) would be more potent than D(2)-selective antagonists at decreasing total cocaine intake relative to disrupting rates of responding. OBJECTIVE: To evaluate the effects of acute administration of seven DA antagonists with varying affinities for D(2) and D(3) receptors in monkeys self-administering cocaine. METHODS: Rhesus monkeys were trained to self-administer intravenous cocaine (0.01-0.3 mg/kg per injection) under a fixed-interval (FI) 5-min schedule during daily 4-h sessions. The use of a FI schedule allowed for independent assessment of rate effects and changes in reinforcement frequency as a consequence of drug pretreatments. The compounds examined, in order of D(3) binding affinity, were: 2,3-dimethoxy-N-(9-p-fluorobenzyl)-azabicyclo[3.3. 1]nonan-3beta-yl benzamide (MABN) = eticlopride = 5-bromo- 2, 3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin-4-yl]benz-amide (BBP) > spiperone > fluoroclebopride (FCP) > 2, 3-dimethoxy-N-(p-fluorobenzyl)piperdin-4-yl benzamide (MBP) > haloperidol. RESULTS: In the absence of any pretreatments, cocaine-maintained responding varied as a function of dose and was characterized as an inverted U-shaped function, while cocaine intake increased in a dose-related fashion. When the dose of cocaine that maintained peak rates was available, all DA antagonists decreased response rates and cocaine intake in a dose- dependent manner. Increases in cocaine dose attenuated the effects of the DA antagonists, resulting in rightward shifts of the cocaine dose-response curves. Based on the ratio of behavioral potency at decreasing response rates relative to intake (ED(50) rate/ED(50) intake) when the highest cocaine dose was available, the order of potency and ED(50) ratio values were: MABN (2.5) > eticlopride (1. 63) > BBP = spiperone (1.5) > FCP (1.35) > MBP = haloperidol (0.89). This order parallels each compound's affinity at D(3) receptors (r(2)=0.84) to a greater degree than D(2) receptor affinity (r(2)=0. 34). CONCLUSIONS: These results, using a FI schedule of cocaine self-administration, suggest that D(3) receptor antagonists are more likely to selectively decrease intake relative to response rates than D(2) receptor antagonists.

Animals↗
PubMed2006

Highly potent and selective phenylmorphan-based inverse agonists of the opioid delta receptor.

We recently reported the discovery of (+)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl-(1-phenyl-1-cyclopentane)carboxamide [(+)-KF4, (+)-5] as a novel chemotype possessing potent antagonist activity at the delta opioid receptor. Additional SAR studies involving changes to both the 2-amino and 7-amido N-substituents using this same (+)-morphan scaffold have revealed compounds with improved potency and selectivity for the delta opioid receptor. The highly potent and selective 2,2-dimethylphenylacetamide analogue (+)-N-[(1S,4R,5R,7S)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-2-methyl-2-phenylpropanamide (13d, delmorphan-A) showed picomolar inhibitory potency (Ke = 0.1 nM) in the [35S]GTPgammaS functional assay with delta opioid receptor selectivity ratios of 103- and 132-fold versus the mu and kappa opioid receptors, respectively. The compounds showed no agonist activity at any of the three opioid receptors; however, measurements of delta inverse agonist activity within this series illustrated a broad range of negative efficacy and IC50 values 650-fold more potent than the prototypical delta opioid receptor inverse agonist ICI 174,864 (22).

Animals↗
PubMed2006

Synthesis of neplanocin F analogues as potential antiviral agents.

Neplanocin F is a natural carbocyclic nucleoside. Herein, we describe the synthesis and antiviral activity of (+/-)-5'-deoxy-neplanocin F analogues. The key intermediate 4, synthesized from the commercially available (+/-)-2-azabicyclo[2.2.1]-hept-5-en-3-one (ABH), was utilized to prepare the target nucleosides. Among the target compounds, 5'-deoxyneplanocin F adenine exhibited moderate anti-HIV activity in human lymphocytes without any marked cytotoxicity.

Adenosine↗
PubMed2005

Approaches to syn-7-substituted 2-azanorbornanes as potential nicotinic agonists; synthesis of syn- and anti-isoepibatidine.

[reaction: see text] Coupling of N-Boc-7-bromo-2-azabicyclo[2.2.1]heptane with aryl and pyridyl boronic acids incorporates aryl and heterocyclic substituents at the 7-position and leads to a preference for syn over anti stereoisomers. Incorporation of a chloropyridyl group followed by N-deprotection gives syn-isoepibatidine. Facial selectivity in attack on 7-keto-2-azanorbornanes depends heavily on the N-protecting group leading to the first syn-7-hydroxy-2-azabicyclo[2.2.1]heptane derivative.

Aza Compounds↗