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At least 757 records · Page 42Linked to original sources
PubMed2006

A common pumiliotoxin from poison frogs exhibits enantioselective toxicity against mosquitoes.

Neotropical poison frogs (Dendrobatidae) contain a variety of lipophilic alkaloids in their diffusely distributed cutaneous glands, including a major class of compounds known as pumiliotoxins. Pumiliotoxins are highly toxic and are believed to protect frogs against predators. Their potential activity against ectoparasites, however, has not been investigated. We tested female yellow fever mosquitoes (Aedes aegypti) for responses to 8-hydroxy-8-methyl-6-(2'-methylhexylidene)-1-azabicyclo[4.3.0]nonane, designated pumiliotoxin 251D [PTX (+)-251D], a skin alkaloid present in all genera of dendrobatids and in other anurans, and to its unnatural enantiomer, PTX (-)-251D. Both enantiomers of PTX 251D presented on silicone feeding membranes reduced landing and feeding by A. aegypti, but PTX (+)-251D did so at lower concentrations. PTX (+)-251D also induced toxicosis, shown when mosquitoes failed to fly off membranes. Similarly, mosquitoes confined with copper wires coated with PTX (+)-251D exhibited greater latencies to fly off the substrate and a higher incidence of leg autotomy than did those confined with the (-)-enantiomer. Our results on the contact toxicities of PTX 251D enantiomers parallel those reported for mice injected with them. The presentation of serial dilutions of PTX (+)-251D to A. aegypti revealed a minimum toxic concentration of 0.1 microg/cm2. This value is substantially lower than that estimated for the cutaneous abundance of this compound in some frogs, an observation consistent the function of PTX 251D in anuran chemical defense against ectoparasitic arthropods.

Alkaloids↗
PubMed2005

Diastereoselectivity enhancement in the 1,3-cycloaddition of beta-lactam aldehydes. Application to the synthesis of enantiopure indolizidinone amino esters.

[reaction: see text] Enantiopure alpha-alkoxy beta-lactam acetaldehydes were prepared via the thiazole-based one-carbon homologation. The 1,3-dipolar cycloaddition reaction involving alpha-alkoxy beta-lactam acetaldehyde-derived azomethine ylides gave with excellent diastereoselectivity highly functionalized 2-azetidinone-tethered prolines, which were directly used for the first preparation of azabicyclo[4.3.0]nonane (indolizidinone) amino esters from beta-lactams.

Acetates↗
PubMed1991

The antiemetic profile of Y-25130, a new selective 5-HT3 receptor antagonist.

Y-25130( (+/-)N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro - 2H-1,4-benzoxazine-8-carboxamide hydrochloride) is a potent and selective 5-HT3 receptor antagonist free of dopamine receptor blocking activity. This compound was effective against emesis induced in animals by cytotoxic drugs or by total body X-radiation. When given prophylactically, the doses required to completely inhibit cisplatin-induced emesis in dogs and doxorubicin and cyclophosphamide-induced emesis in ferrets were 0.1 and 0.3 mg/kg i.v., respectively. Y-25130, at the dose of 0.3 mg/kg i.v., almost completely inhibited X-radiation-induced emesis in ferrets. When given during emesis, the doses required to completely inhibit cisplatin-induced emesis in dogs and doxorubicin- and cyclophosphamide-induced emesis in ferrets were 0.1 and 0.3 mg/kg i.v., respectively. The i.v. dose of 0.3 mg/kg of Y-25130 was enough to almost completely inhibit cisplatin-induced emesis in dogs for 24 h. From these results, it is suggested that Y-25130 may become an effective antiemetic drug against emesis induced by anticancer therapy.

Animals↗
PubMed2003

Synthesis and biological activity of 2-carbomethoxy-3-catechol-8-azabicyclo[3.2.1]octanes.

Cocaine inhibits the dopamine transporter and the consequent elevation of dopamine is thought to contribute to the addictive properties of cocaine. Tropane analogues of cocaine, targeted to the dopamine transporter (DAT), are a significant focus of drug design for cocaine addiction medications. Herein, we report the function of the ortho hydroxy substituents in dopamine with respect to the azabicyclo[3.2.1]octane skeleton. The introduction of the o-dihydroxyl functionality led to reduced binding potency at monoamine transporters, rather than enhanced interaction with the DAT. It is therefore likely that the binding site for these compounds on the DAT is not the same as that for dopamine. Notwithstanding the moderate potency of the free catechols (>100 nM), 7 manifested stimulant activity with a duration of effect that exceeded 4 h in a rat locomotor activity assay. Compound 10, a diacetoxy prodrug for 7, substituted fully for cocaine in a rat drug-discrimination paradigm and is now undergoing further investigation as a potential medication for cocaine abuse.

Animals↗
PubMed2001

Synthesis and anti-influenza virus activity of tricyclic compounds with a unique amine moiety.

Several novel tricyclic compounds with a unique amine moiety (1, 2a--i) were designed and prepared based on the structure of triperiden for the development of anti-influenza virus agents. An in vitro antiviral assay showed that 1-(1-azabicyclo[3.3.0]octan-5-yl)-1-(4-fluorophenyl)-1-(2-tricyclo[3.3.1.1(3.7)]decyl)methan-1-ol hydrochloride (2f) has a potent anti-influenza A virus activity. Furthermore, since 2f was well tolerated in mice, 2f is promising as a novel anti-influenza virus agent for humans.

Animals↗
PubMedDate not supplied

Analysis of the in vitro inhibition of murine and human tumor cell growth by pyrazole derivatives and a substituted azabicyclo [3.1.0] hexane-2,4-dione.

3-Ethoxycarbonyl-5-phenyl-1, 3a, 4, 5, 6, 6a-hexahydropyrrolo[3,4-c]pyrazole-4, 6-dione, 2, 2, 6, 6-tetraethyl-1H, 5H-pyrazole[1, 2-a]pyrazole-1, 3, 5, 7-[2H, 6H]-tetraone and 6-ethoxycarbonyl-3-phenyl-3-azabicyclo[3.1.0] hexane-2, 4-dione demonstrated potent cytotoxic activity in the human Tmolt3, Tmolt4 and HL-60 leukemia screens, HuT-78 lymphoma and HeLa suspended uterine carcinoma cell lines. Most notable was the finding that these compounds were significantly more active than the standard cytotoxic agents examined in the MCF-7 breast (ED50 0.2-1.0 microg/ml) and U87MG glioma (ED50 1.3-2. 6 microg/ml) tumor screens. The agents inhibited Tmolt4 leukemia DNA and RVA syntheses after 60 min at 100 microM Multiple enzymes involved with nucleic acid metabolism appeared to be targeted including inhibition of RNA polymerases, ribonucleotide reductase and nucleoside kinase activities, however, inhibition of de novo purine synthesis at the key regulatory enzyme IMP dehydrogenase appeared to be the primary target. The predominant IMPDH isoform (Type II) detected in a number of human cancers, such as leukemias, ovarian and breast, was inhibited by the compounds yielding IC50 values in the microM range. Furthermore, inhibition of IMP dehydrogenase activity led to the selective depletion of dGTP pool levels by two of the compounds. The DNA molecule was not a target of the agents since no alkylation of the bases, cross-linking of the DNA strands or intercalation between base pairs occurred. Yet, the compounds did cause DNA fragmentation after incubating at 100 microuM for 24 h which was consistent with the observed decrease in ct-DNA viscosity.

Animals↗
PubMed1976

2-Azabicyclo (2.2.2)octane analogues of the prodine analgetics.

The synthesis and analgetic activity of analogues of prodine-type analgetics in which the conformation of the piperidine ring is restricted in the boat form using the 2-azabicyclo (2.2.2)octane nucleus are reported. One of these analogues, 2-methyl-6-trans-phenyl-6-cis-propionoxy-2-azabicyclo (2.2.2)octane (3), showed significant analgetic activity (ED50 equals 3.1 mg/kg).

Alphaprodine↗
PubMed2002

Synthesis and biological evaluation at nicotinic acetylcholine receptors of N-arylalkyl- and N-aryl-7-azabicyclo[2.2.1]heptanes.

A new series of N-arylalkyl-substituted 7-azabicyclo[2.2.1]heptanes and N-aryl-substituted 7-azabicyclo[2.2.1]heptanes were synthesized and evaluated as potential ligands for neuronal nicotinic acetylcholine receptors. The in vitro binding affinities (K(i)) of the 7-azabicyclo[2.2.1]heptane derivatives were measured by inhibition of [(3)H]cytisine binding to rat brain tissue. The most potent ligand of the series was found to be N-(3-pyridylmethyl)-7-azabicyclo[2.2.1]heptane (5b, K(i) = 98 nM). The chloro analogue (5a, K(i) = 245 nM) 5a and epibatidine (1) produced dose-dependent analgesia in both hotplate and tail-flick tests when administered subcutaneously. However, when compounds 1 and 5a,b were administered intrathecally, all produced analgesia in the tail-flick test but only 5a produced analgesia in the hotplate test.

Analgesics, Non-Narcotic↗
PubMed2004

2,3-disubstituted 6-azabicyclo[3.2.1]octanes as novel dopamine transporter inhibitors.

A series of cis and trans 3beta-aryl-2-carbomethoxy-6-azabicyclo[3.2.1]octanes, with different substitution at the para-position of the aryl group, were synthesized and examined for reuptake inhibition at the dopamine transporter (DAT). The potency for inhibition of DA reuptake was compared with that of cocaine to determine the significance of the replacement of the 8-azabicyclo[3.2.1]octane (tropane nucleus), displayed in cocaine, for the 6-azabicyclo[3.2.1]octane (normorphan framework). This bicyclic core structure constitutes a novel chemical scaffold in DAT inhibitor design, which may provide new insights into the 3D structure of the DAT and its interaction with cocaine and DA. Among these compounds, the trans-amine series 8 were the most potent ligands at the DAT. In particular, the normorphan analogue 8c (bearing a p-chloro substituent at the beta-aryl group, IC(50)=452 nM) displayed a potency that is in the same range as cocaine (IC(50)=459 nM) itself.

Animals↗
PubMed2003

Antidepressant-like actions of DOV 21,947: a "triple" reuptake inhibitor.

DOV 21,947 [(+)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride] inhibits the reuptake of [3H]serotonin, [3H]norepinephrine, and [3H]dopamine in human embryonic kidney (HEK) 293 cells expressing the corresponding human recombinant transporters (IC(50) values of 12, 23, and 96 nM, respectively). This compound also inhibits [125I]RTI 55 (3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester) binding to the corresponding transporter proteins in membranes prepared from these cells (K(i) values of 99, 262, and 213 nM, respectively). DOV 21,947 reduces the duration of immobility in the forced swim test (using rats) with an oral minimum effective dose of 5 mg/kg. This antidepressant-like effect manifests in the absence of significant increases in motor activity at doses of up to 20 mg/kg. DOV 21,947 also produces a dose-dependent reduction in immobility in the tail suspension test, with a minimum effective oral dose of 5 mg/kg. The ability of DOV 21,947 to inhibit the reuptake of three biogenic amines closely linked to the etiology of depression may result in a therapeutic profile different from antidepressants that inhibit the reuptake of serotonin and/or norepinephrine.

Animals↗