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At least 523 records · Page 29Linked to original sources
PubMed1989

Inhibition of animal models of autoimmune disease and the induction of non-specific suppressor cells by SK&F 105685 and related azaspiranes.

SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine+ ++ dihydrochloride), administered orally to adjuvant arthritic (AA) rats inhibited immune-mediated hindpaw inflammation with an ED50 of 20 mg/kg/day. Both prophylactic and therapeutic administration were effective in this model. In addition, SK&F 105685 inhibited skin wheal responses to purified protein derivative (PPD) of tuberculin in AA rats and the development of hindleg paralysis associated with experimental allergic encephalomyelitis (EAE). Spleens of normal rats treated with SK&F 105685 were found to contain a population(s) of suppressor cells (SC) which inhibited the response of normal cells to Concanavalin A (Con A) in co-culture assays. The association between SC induction and anti-arthritic activity was determined by evaluating a series of chemically related azaspiranes in the AA rat model and for SC induction in normal rats. A statistically significant correlation was demonstrated (r = 0.79, P less than 0.001), indicating that SC induction may be responsible for the therapeutic activity of these compounds.

Adjuvants, Immunologic↗
PubMed2005

Antiinsectan decaturin and oxalicine analogues from Penicillium thiersii.

Three new oxalicine and decaturin analogues (6-8) have been isolated from organic extracts of Penicillium thiersii, along with the known compounds oxalicines A and B. These compounds (4-8) are members of a group of unique natural products containing terpenoid and pyridine moieties. The structures of the new compounds were elucidated by analysis of NMR and MS data. Most of these metabolites exhibit potent antiinsectan activity against the fall armyworm (Spodoptera frugiperda).

Animals↗
PubMed1998

Spirofungin, a new antifungal antibiotic from Streptomyces violaceusniger Tü 4113.

A new secondary metabolite was detected in the culture filtrate and extracts of Streptomyces violaceusniger Tü 4113 by HPLC-diode-array and HPLC-electrospray-mass-spectrometry screening. The compound named spirofungin has a polyketide-spiroketal structure and shows various antifungal activities, particularly against yeasts.

Antifungal Agents↗
PubMed2005

Autoradiographic characterisation of [35S]GTPgammaS binding stimulation mediated by 5-HT1B receptor in postmortem human brain.

G-protein activation mediated by 5-HT1B receptors was studied in human brain by [35S]GTPgammaS autoradiographic methods. 5-HT (10 microM) increased [35S]GTPgammaS binding in caudate-putamen nucleus, globus pallidus, dentate gyrus, CA1, entorhinal cortex and substantia nigra. In basal ganglia and midbrain, this effect was blocked by GR 127935 (5-HT(1B/1D) antagonist). In contrast, WAY 100635 (selective 5-HT1A antagonist) reversed the effect of 5-HT in hippocampus and entorhinal cortex. Therefore, a detailed pharmacological study was carried out in basal ganglia and substantia nigra using 5-HT and the 5-HT(1B/1D) agonists GTI and CP 93129. In these areas, these agonists stimulated [35S]GTPgammaS binding in a concentration-dependent manner, with no significant differences in the potency for a given structure. Furthermore, GTI was more potent in the putamen than in globus pallidus. In caudate-putamen, the three agonists showed the same efficacy, while in globus pallidus and substantia nigra the efficacy of 5-HT was higher than GTI and CP 93129. The selective 5-HT1B antagonist SB-224289 inhibited GTI- and CP 93129-stimulated [35S]GTPgammaS binding in basal ganglia and substantia nigra, while coincubation with BRL 15572 (selective 5-HT1D antagonist) did not result in any significant change. Here we report the anatomical pattern of distribution of 5-HT1B-dependent functionality by using specific pharmacological tools in human brain sections.

Aged↗
PubMed2004

Recognition of privileged structures by G-protein coupled receptors.

Privileged structures are ligand substructures that are widely used to generate high-affinity ligands for more than one type of receptor. To explain this, we surmised that there must be some common feature in the target proteins. For a set of class A GPCRs, we found a good correlation between conservation patterns of residues in the ligand binding pocket and the privileged structure fragments in class A GPCR ligands. A major part of interior surface of the common ligand binding pocket of class A receptors, identified in many GPCRs, is lined with variable residues that are responsible for selectivity in ligand recognition, while other regions, typically located deeper into the binding pocket, are more conserved and retain a predominantly hydrophobic and aromatic character. The latter is reflected in the chemical nature of most GPCR privileged structures and is proposed to be the common feature that is recognized by the privileged structures. Further, we find that this subpocket is conserved even in distant orthologs within the class A family. Three pairs of ligands recognizing widely different receptor types were docked into receptor models of their target receptors utilizing available structure- activity relationships and mutagenesis data. For each pair of ligands, the ligand-receptor complexes reveal that the nature of the privileged structure binding pocket is conserved between the two complexes, in support of our hypothesis. Only part of the privileged structures can be accommodated within the conserved subpocket. Some contacts are established between the privileged structure and the nonconserved parts of the binding pocket. This implies that any one particular privileged structure can target only a subset of receptors, those complementary to the full privileged structure. Our hypothesis leads to a valuable novelty in that ligand libraries can be designed without any foreknowledge of the structure of the endogenous ligand, which in turn means that even orphan receptors can in principle now be addressed as potential drug targets.

Amino Acid Sequence↗
PubMed2003

Paraherquamides, brevianamides, and asperparalines: laboratory synthesis and biosynthesis. An interim report.

Studies from our laboratories on the paraherquamide, brevianamide, and asperparaline families of natural products are reviewed. It has been proposed that the unique core ring system that is common to this family of compounds arises by a biological intramolecular Diels-Alder cycloaddition reaction. Key biosynthetic studies are described, along with classical synthetic approaches as well as those inspired by Nature for the synthesis of these interesting molecules.

Alkaloids↗
PubMed1997

Bioactive iridoids and a new lignan from Allamanda cathartica and Himatanthus fallax from the Suriname rainforest.

Bioassay-guided fractionation of the EtOAc extract of both Allamanda cathartica and Himatanthus fallax (Apocynaceae) using the Sc-7 yeast strain resulted in the isolation of the weakly cytotoxic isoplumericin and plumericin. In addition, the new lignan 7(R)-methoxy-8-epi-matairesional and three known compounds, plumieride, matairesinol, and pinoresinol, were isolated from H. fallax.

Animals↗
PubMed1994

S 12340: a potent inhibitor of the oxidative modification of low-density lipoprotein in vitro and ex vivo in WHHL rabbits.

Oxidative modification of low-density lipoprotein (LDL) is thought to play a key role in the formation of foam cells and in the initiation and progression of the atherosclerotic plaque. After evaluation of a large number of original drugs, S 12340 was found to be the most potent compound in inhibiting in a dose-dependent manner the human LDL oxidative modification induced either by copper ions or by cultured endothelial cells. Both the electrophoretic mobility and the thiobarbituric acid reactive substances returned to almost normal values in the presence of 0.5 microM of S 12340. Watanabe heritable hyperlipidemic rabbits were treated orally for 3 days or for 1 month with S 12340 to evaluate the potential protective effect of the compound on LDL oxidative modification induced ex vivo. Purified LDL from placebo and treated rabbits were submitted to oxidation, and S 12340 was effectively able to protect LDL in a dose-dependent manner and at doses as low as 10 mg/kg/day. Purified LDL from animals sacrificed at various times after oral administration of S 12340 were protected against oxidation for at least 6 h after the last administration of the compound. These findings are in good agreement with the plasma and LDL levels of S 12340 in these WHHL rabbits. S 12340, probucol and vitamin E were all able to decrease the optical density of the 1,1-diphenyl-2-picrylhydrazyl solution, demonstrating their free radical scavenging properties. The pharmacological properties of the compound suggest that S 12340 may be of potential interest for a new therapeutic approach to atherosclerosis.

Animals↗
PubMed2001

Regulation of GABA release by nicotinic acetylcholine receptors in the neonatal rat hippocampus.

1. The whole-cell configuration of the patch-clamp technique was used to study the modulation of giant depolarizing potentials (GDPs) by nicotinic acetylcholine receptors (nAChRs) in CA3 hippocampal neurons in slices from postnatal day (P) 2-6 rats. 2. Bath application of nicotine increased GDP frequency in a concentration-dependent manner. For example, nicotine (0.5-1 microM) enhanced GDP frequency from 0.05 +/- 0.04 to 0.17 +/- 0.04 Hz. This effect was prevented by the broad-spectrum nicotinic receptor antagonist dihydro-beta-erythtroidine (DHbetaE, 50 microM) and partially antagonized by methyllycaconitine (MLA, 50 nM) a competitive antagonist of alpha7 nAChRs. GDP frequency was also enhanced by AR-17779 (100 microM), a selective agonist of alpha7 nAChRs. 3. The GABA(A) receptor antagonist bicuculline (10 microM) and the non-NMDA glutamate receptor antagonist DNQX (20 microM) blocked GDPs and prevented the effects of nicotine on GDPs. In the presence of DNQX, nicotine increased GABA-mediated synaptic noise, indicating that this drug may have a direct effect on GABAergic interneurons. 4. Bath application of edrophonium (20 microM), a cholinesterase inhibitor, in the presence of atropine (1 microM), increased GDP frequency, indicating that nAChRs can be activated by ACh released from the septo-hippocampal fibres. This effect was prevented by DHbetaE (50 microM). 5. In the majority of neurons tested, MLA (50 nM) and DHbetaE (50 microM) reduced the frequency of GDPs with different efficacy: a reduction of 98 +/- 11 and 61 +/- 29 % was observed with DHbetaE and MLA, respectively. In a subset of cells (40 % in the case of MLA and 17 % in the case of DHbetaE) these drugs induced a twofold increase in GDP frequency. 6. It is suggested that, during development, nAChRs modulate the release of GABA, assessed as GDPs, through distinct nAChRs. The rise of intracellular calcium via nAChRs would further strengthen GABA-mediated oscillatory activity. This can be crucial for consolidation of synaptic contacts and for the fine-tuning of the developing hippocampus.

Acetylcholine↗
PubMed2002

Spirocyclic NK(1) antagonists I: [4.5] and [5.5]-spiroketals.

A series of novel spiroketal-based NK(1) antagonists is described. The effect of modifications to the spiroether ring and aromatic substituents are discussed, leading to the identification of compounds with high affinity and excellent CNS penetration.

Neurokinin-1 Receptor Antagonists↗
PubMed1998

Inhibitors of glycogen phosphorylase b: synthesis, biochemical screening, and molecular modeling studies of novel analogues of hydantocidin.

The synthesis and biochemical screening of four novel spironucleosides 1-4 against rabbit liver glycogen phosphorylase b (Gpb), along with molecular modeling studies on compound 2 and its 4-hydroxy analogue VII, have been presented. Gpb is a key enzyme of glycogen metabolism, and is known to be involved in the control of diabetes mellitus. The general strategy for synthesis involved base-catalyzed condensation of diethyl 2,4-dioxoimidazolidine-5-phosphonate (5) with either 2-deoxy-D-ribose or D-ribose, followed by sequential reactions involving ring-closure with phenylselenenyl chloride and reduction with tri-n-butyltin hydride catalyzed by azobisisobutyronitrile. Compounds 2 and 4 were found to be weak competitive inhibitors of Gpb, whereas 1 and 3 were inactive.

Animals↗
PubMed1999

The molecular structure of 2alpha-hydroxyneoanisatin and structure-activity relationships among convulsant sesquiterpenes of the seco-prezizaane and picrotoxane types.

The molecular structure of 2alpha-hydroxyneoanisatin, a positional isomer of the potent neurotoxin anisatin, was determined by X-ray crystallographic analysis. This compound and four further seco-prezizaane type sesquiterpene lactones previously isolated from Illicium floridanum, which represent different structural types with respect to the mode of cyclisation, did not induce anisatin/picrotoxinin-like convulsions in mice. Based on these results and literature data for other seco-prezizaanes, structural requirements for convulsant activity are discussed. Comparison of the three dimensional molecular shape and electrostatic properties of active and inactive seco-prezizaane type lactones with compounds of the picrotoxane type resulted in the identification of a common pharmacophore structure for these different skeletal classes of convulsant natural products.

Animals↗
PubMed1995

In-vitro activity of purpuromycin and MDL 63,604 against microorganisms that cause vaginitis and vaginosis.

Purpuromycin and its semi-synthetic derivative MDL 63,604 had in-vitro activity similar to that of amphotericin B against isolates of Candida albicans. MDL 63,604 had activity similar to that of metronidazole against Trichomonas vaginalis. Both compounds were very active against most species of Gram-positive and Gram-negative anaerobes and against Gardnerella vaginalis. MDL 63,604 had significantly lower MICs than purpuromycin against T. vaginalis and most of the bacteria, probably due to antagonism of purpuromycin's activity by medium supplements (blood or serum). Purpuromycin or related compounds may have a potential role in the topical treatment of vaginitis and vaginosis.

Amphotericin B↗
PubMed1990

Synthesis of acetylenic spirobutenolide derivatives and evaluation of their growth inhibitory effect on cells in culture.

Acetylenic spirobutenolide amides and esters and their Mannich bases were synthesized to evaluate their growth inhibitory effect. The biological tests have used both normal and transformed cells and they have shown the selectivity of the prepared compounds. The ester derivatives presented the best selectivity comparable to that of daunorubicin.

Antineoplastic Agents↗
PubMed2004

Effect of repeated administration of TRK-820, a kappa-opioid receptor agonist, on tolerance to its antinociceptive and sedative actions.

Repeated administration of micro-opioid receptor agonist, morphine induces tolerance not only to the antinociceptive effect but also to other pharmacological effects, resulting in shortened working duration and decreased efficacy. But less is known about kappa-opioid agonist-induced tolerance. The tolerance-development potency of kappa-opioid receptor agonists with a focus on TRK-820 was characterized. After five administrations of kappa-opioid receptor agonists, TRK-820 (0.1-0.8 mg/kg), U-50,488H (10-80 mg/kg) and ICI-199,441 (0.025-0.2 mg/kg) subcutaneously over 3 days, tolerance to the antinociceptive effects, assessed by an acetic acid-induced abdominal constriction test, developed in a repeated dose-dependent manner. The tolerance-development potency of TRK-820 was the least among these kappa-opioid receptor agonists. Similarly, TRK-820 and U-50,488H induced tolerance to their sedative effects as judged by a wheel-running test in mice. Greater tolerance was developed to the sedative effect than to the antinociceptive effect in both compounds. After repeated administration, the number of kappa-opioid receptors in the mouse brain was reduced by U-50,488H (80 mg/kg) but not by TRK-820 (0.4 mg/kg). There was no change of the affinity by the treatment with both compounds. These results demonstrated that the kappa-opioid receptor agonists developed tolerance both to the antinociceptive and the sedative effects, though the tolerance to the sedative effect developed more readily than tolerance to the antinociceptive effect. The difference in the potency for down-regulating the kappa-opioid receptors in the brain may account for the tolerance-development potency of the compounds.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1988

Atypical antipsychotic agents: patterns of activity in a series of 3-substituted 2-pyridinyl-1-piperazine derivatives.

A series of 3-substituted 2-pyridinyl-1-piperazine derivatives have been appended to cyclic imide groups and evaluated for their potential antipsychotic activity. The dopamine receptor affinities of these target molecules, as well as their ability to block apomorphine-induced stereotypy or reverse neuroleptic-induced catalepsy, was dependent on the lipophilic and electronic characteristics of the substituent situated on the pyridine ring. Groups with + omega and - phi values were most consistent with the desired biological profile of the target molecules, the cyano moiety being the optimum choice. Evaluation of compound 12 in a monkey model of amphetamine psychosis, and the regional selectivity it expresses for the A10 dopaminergic cell bodies in electrophysiological experiments, suggest this compound would be an atypical antipsychotic agent with few side effects.

Animals↗