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Biomedical subjects

A Brossi

Publications and source records attributed to A Brossi.

At least 55 records · Page 3Linked to original sources
PubMed1989

Structure of an ether dimer of deoxydihydroqinghaosu, a potential metabolite of the antimalarial arteether.

C30H49O7, Mr = 518.69, triclinic, P1, a = 9.013 (2), b = 10.520 (2), c = 15.187 (3) A, alpha = 93.3 (2), beta = 93.73 (1), gamma = 95.88 (2) degrees, V = 1426.2 (5) A3, Z = 2, Dx = 1.21 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.65 mm-1, F(000) = 564, T = 295 K, final R = 0.043, wR = 0.042 for 3842 observed reflections. The dimer is formed such that the deoxyarteether moieties are cis to one another. Attempts to determine the absolute configuration of the molecule were inconclusive so the conformation corresponding to that found for qinghaosu was used for the refinement. Both halves of the dimer have the same chirality with five of the seven asymmetric carbons having an S conformation and two (C5 and C6) having an R conformation.

Antimalarials↗
PubMed1989

Comparative inhibitory effects of various physostigmine analogs against acetyl- and butyrylcholinesterases.

A number of carbamoyl- and N(1)-substituted analogs of physostigmine were synthesized and their in vitro potencies (IC50 values) vs. human erythrocyte and brain (cerebral cortex and caudate nucleus) acetylcholinesterase (AChE) and electric eel AChE and against human brain and plasma butyrylcholinesterase (BChE) were compared to the potencies of physostigmine and other traditional anticholinesterases. In general, increasingly hydrophobic, simple nonbranching carbamoyl groups (as in octyl-, butyl- and benzylcarbamoyl eseroline) did not greatly alter potency vs. AChE whereas increasingly hydrophobic N(1)-substitutions [i.e., N(1)-allyl-, -phenethyl and -benzylphysostigmine] decreased potency vs. AChE. In contrast, increasing the hydrophobicity of both the carbamoyl and N(1) groups increased the potency of the compound against BChE. Furthermore, quaternarization at the N(1) position (physostigmine methosulfate) increased potency vs. AChE but reduced potency vs. BChE. Bulky, branched carbamoyl groups (e.g., N-benzyl-N-benzyl-allophanyl eseroline) were all poor anticholinesterases. N-phenylcarbamoyl eseroline was as potent as benzylcarbamoyl eseroline against AChE yet was 50 to 100 times less potent than the benzyl analog vs. BChE. Therefore, the phenyl substitution appears to increase greatly the selectivity of the compound for AChE. Although it is not possible to determine whether physostigmine analogs that are potent in vitro might be of interest in vivo, these results do show that the structure of physostigmine can be changed significantly while retaining biological activity.

Animals↗
PubMed1988

Carbamate analogues of (-)-physostigmine: in vitro inhibition of acetyl- and butyrylcholinesterase.

Reaction of (-)-eseroline (1) with alkyl, aryl and aralkylisocyanates afforded a series of carbamate analogues of (-)-physostigmine (2) which were assayed for inhibition of acetyl- and butyrylcholinesterase (AChE and BChE, respectively) in vitro. Included in this study were two N-alkyl-substituted carbamates 9 and 14 obtained from (-)-eseroline (1) with dialkylcarbamoyl chlorides, and allophanates 12 and 13 obtained as by-products in the reaction of 1 and benzylcarbamoyl eseroline (8) with benzyl isocyanate. Whereas none of the analogues studied was more potent than 2 against electric eel AChE, and carbamates 6, 7 and 8 were all more than 3 times more potent against human plasma BChE than 2.

Acetylcholinesterase↗
PubMed1988

The importance of the phenyl-tropolone 'aS' configuration in colchicine's binding to tubulin.

Measuring ellipticities of (+/-)-colchicine and (+/-)-deacetamidocolchicine in the presence of tubulin afforded net positive CD bands with maxima at 340 nm resulting from reduction of the negative ellipticities upon binding of (-) enantiomers to the protein. Results of optical studies together with earlier NMR conformational analysis of these molecules substantiate the hypothesis that colchicinoids bind to tubulin with the phenyl-tropolone moiety in the 'aS' configuration. Natural colchicine which binds to tubulin, therefore, should be referred to as (-)-(aS,7S)-colchicine.

Animals↗
PubMed1988

Enantiomer (+)physostigmine prevents organophosphate-induced subjunctional damage at the neuromuscular synapse by a mechanism not related to cholinesterase carbamylation.

The natural alkaloid (-)PHY is a reversible anticholinesterase carbamate, but in contrast, its optical isomer (+)PHY, is a very weak anticholinesterase. We have shown that treatment of rats with atropine and (-)PHY prior to injections of a lethal dose of the irreversible organophosphate sarin (0.13 mg/kg) not only protected 100% of the animals from lethality but also reduced the size of the subneural lesions of the nicotinic synapses of skeletal muscle. Similar protection against lethality is provided by pretreatment with (+)PHY. At the concentration used (0.3 mg/kg), there was no detectable inhibition of AChE activity. We have examined the protection afforded by (+)PHY or (-)PHY against lethality and myopathy due to organophosphate agents such as sarin. The major alterations in the soleus motor endplates 1 hr after drug treatment were as follows: (1) A single sublethal dose of sarin (0.08 mg/kg) produced enlarged, blistered, and severely disrupted subjunctional regions, with muscle damage extending beyond the endplate to include myofiber necrosis and subsequent phagocytosis; (2) (+)PHY (0.3 mg/kg) produced no obvious damage in the postjunctional region; (3) (-)PHY (0.1 mg/kg) had a selective effect in inducing irregularities of the subjunctional sarcomere band patterns without any gross vacuolization; (4) light microscopic data indicated that the combination of atropine and (+)PHY, or of atropine and (-)PHY (0.1 mg/kg), 30 min prior to a lethal dose of sarin, offered dramatic reduction in the average dimension of lesions. Lesions were detectable in most endplates but recognizable changes were markedly less severe than those seen in sarin myopathy. Few instances of extensive muscle damage and myofiber necrosis were visible.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Neurotoxic damage to the nigrostriatal system in rats following intranigral administration of MPDP+ and MPP+.

Unilateral intranigral administration of the oxidative metabolites of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenyl-dihydropyridine (MPDP+) or 1-methyl-4-phenylpyridine (MPP+) produced dose-dependently a depletion of dopamine in the ipsilateral striatum of rats two weeks following treatment. d-Amphetamine and apomorphine induced circling toward the lesioned side in these unilaterally treated animals. No contralateral circling behavior was observed after challenging with apomorphine. This dopamine lesioning effect of MPP+ was not blocked by pretreatment of animals with a dopamine uptake blocker, GBR 12909. Furthermore, MPP+ increased the 45Ca accumulation into cells at the site of injection and produced "nonspecific" cell membrane and/or cytotoxic damage seen by histological procedures. These results indicate that MPDP+ and MPP+ produced localized cytotoxic damage to nigrostriatal neurons, caused a decrease in striatal dopamine, and disrupted the nigrostriatal system's functioning following intranigral administration to rats. It is postulated that the cationic surfactant properties of MPDP+ and MPP+ might contribute to its neurotoxic effects.

1-Methyl-4-phenylpyridinium↗
PubMed1988

Synthesis and anticholinesterase activity of (-)-N1-norphysostigmine, (-)-eseramine, and other N(1)-substituted analogues of (-)-physostigmine.

(-)-N1-Benzylnorphysostigmine (4), prepared from synthetic (-)-O-methyl-N1-noreseroline (1) by N-benzylation, ether cleavage, and reaction of (-)-N1-benzylnoreseroline (3) with methyl isocyanate, was the intermediate used to prepare the title compounds. Catalytic debenzylation of 4 afforded (-)-N1-norphysostigmine (5), and (-)-eseramine (6) was obtained by reaction of 5 with methyl isocyanate. Reductive N-methylation of 5 gave (-)-physostigmine (9) while reaction of 5 with allyl bromide and phenethyl bromide afforded carbamates 7 and 8, respectively. Data on the in vitro potencies (IC50) and activities of certain of these compounds (4-8) as inhibitors of electric eel acetyl cholinesterase are reported. (-)-N1-Norphysostigmine (5) was found to be similarly potent against AChE as (-)-physostigmine (9).

Animals↗
PubMed1988

Arteether, a new antimalarial drug: synthesis and antimalarial properties.

Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than quinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether(6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients.

Animals↗
PubMed1988

Structure-activity relationship of reversible cholinesterase inhibitors: activation, channel blockade and stereospecificity of the nicotinic acetylcholine receptor-ion channel complex.

1. We have shown that all cholinesterase (ChE) inhibitors, in addition to their well-known anti-ChE activity, have multiple effects on the nicotinic acetylcholine receptor-ion channel (AChR) macromolecule resulting from interactions with the agonist recognition site and with sites located at the ion channel component. Activation, competitive antagonism and different types of noncompetitive blockade occurring at similar concentration ranges and contributing in different proportions result in complex and somewhat unpredictable alterations in AChR function. The question is now raised as to how each effect of these compounds contributes to their antidotal property against organophosphorus (OP) poisoning, and what set of actions makes one reversible ChE inhibitor a better antidote. Many lines of evidence support the importance of direct interactions with various sites on the AChR: 1) morphological and toxicological studies with (+) physostigmine showed that anti-ChE activity is not essential to protect animals against toxicity by irreversible ChE inhibitors; 2) (-)physostigmine is far more effective against OP poisoning; 3) open channel blockers such as mecamylamine with no significant anti-ChE activity enhance the protective action of (-)physostigmine; 4) neostigmine, pyridostigmine, (-)physostigmine and (+)physostigmine showed qualitatively and quantitatively distinct toxicity and damage to endplate morphology and function. 2. In prophylaxis and during the very early phase of OP poisoning, carbamates, especially (-)physostigmine combined with mecamylamine and atropine, could protect almost 100% of the animals exposed to multiple lethal doses of OPs. Electrophysiological data showed that (-)physostigmine, among several reversible ChE inhibitors, showed greater potency in depressing both endplate current (EPC) peak amplitude and tau EPC. Therefore, concerning neuromuscular transmission, it seems that the higher the potency of a drug in reducing endplate permeability, the better is its protection against OP toxicity. A reversible open channel blockade combined with some agonist property helps to decrease the effect of ACh at its agonist site and to reduce the ion permeability of open channels. It should be pointed out that, during the later phase of OP poisoning, AChR desensitization should be most prevalent. Thus, a drug that can remove the AChR from this rather irreversible state to a more reversible blocked state should be a better protector. Indeed, oximes such as 2-PAM and a more potent analog, HI-6, produce multiple alterations in AChR function that comprise increased channel activation and open-channel blockade.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Photooxidation products of primaquine. Structure, antimalarial activity and hemolytic effects.

Photooxidation of primaquine (1) and 5-hydroxyprimaquine (5) afforded a blue dye for which o-quinone structure 4 was elaborated. Similar oxidation of N-ethoxyacetylprimaquine (10) afforded o-quinone 11. Tissue schizontocidal activity of 4 and 11, and bisquinolylmethine 3 prepared earlier, showed that none of them had noteworthy antimalarial activity, but all three produced methemoglobin.

Animals↗
PubMed1987

MPTP metabolites inhibit rat brain glutathione S-transferases.

1-Methyl-4-phenyl-2,3-dihydropyridinium and 1-methyl-4-phenyl-pyridinium species, metabolites of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, non-competitively inhibit glutathione S-transferases of rat brain in vitro. The Ki values for 1-methyl-4-phenyl-2,3-dihydropyridinium bromide and 1-methyl-4-phenyl-pyridinium bromide are 0.67 and 0.3 mM, respectively. Inhibition of these enzymes may lead to impairment of cellular defense mechanisms.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Antimalarial activity and inhibition of monoamine oxidases A and B by exo-erythrocytic antimalarials. Optical isomers of primaquine, N-acylated congeners, primaquine metabolites and 5-phenoxy-substituted analogues.

When the terminal amino group in the side chain of primaquine was blocked with an ethoxyacetyl group shown in 2, or eliminated by oxidative deamination to carboxylic acid 3, the antimalarial effect was markedly reduced in a screening assay which measures tissue schizonticidal activity. The optical isomers 1A and 1B of primaquine had similar antimalarial potency to the racemic mixture but 1B appeared less toxic. The 5-phenoxy-substituted analogue 4, belonging to a new class of antimalarials, showed similar potency in the assays to either 1A or 1B but seemed less cytotoxic than (+/-)-primaquine. Compounds 1A and 1B were found to be competitive inhibitors of human monoamine oxidase (MAO) A and B (Ki range 103-225 microM), but 4 showed 10-30-fold greater competitive inhibition of MAO A (Ki = 6.8 microM) and 40-90-fold greater non-competitive inhibition of MAO B (Ki = 2.3 microM).

Animals↗
PubMed1987

Separation of tubulin-binding and anti-inflammatory activity in colchicine analogs and congeners.

The effects of colchicine and its analogs on the carrageenin-induced footpad edema in rats were investigated. The anti-inflammatory effects of colchicine analogs were measured at 3 and 5 hr after the carrageenin injection. Colchicine, 1-demethylcolchicine and 3-demethylcolchicine markedly inhibited the carrageenin edema whereas 2-demethylcolchicine was much less active. Thiocolchicinoids, having a thiomethyl group at C-10 instead of a methoxy group, were considerably less potent. These results suggest that the presence of methoxy groups at C-2 and C-10 in colchicine is necessary to maintain anti-inflammatory activity. Inactivity of deacetylcolchicine indicates that substitution of the amino group at C-7 with electron withdrawing groups is also important. Significant inhibition of carrageenin edema and strong binding to tubulin in vitro were manifested by colchicine, 3-demethylcolchicine, N-butyryldeacetylcolchicine and colchifoline. On the other hand, N-carbethoxydeacetylcolchicine which did bind well to tubulin, did not show much effect on the carrageenin edema. These results suggest that the anti-inflammatory action of colchicinoids may not be regulated through the microtubule system.

Animals↗
PubMed1987

A novel synthesis of colchicide and analogues from thiocolchicine and congeners: reevaluation of colchicide as a potential antitumor agent.

Desulfurization of thiocolchicine with Raney nickel in a hydrogen atmosphere yielded tetrahydromethoxycolchicine (2), which was readily separated from unreacted thiocolchicine by chromatography and was smoothly oxidized to 10-demethoxycolchicine (colchicide) by Pd/C in refluxing toluene. Several analogues of colchicide were prepared from the corresponding thiocolchicines by this procedure. Treatment of colchicide with concentrated sulfuric acid yielded 2-demethylcolchicide. Colchicide and its analogues were found to be inactive in a tubulin-binding assay. Evidence is presented that colchicide prepared earlier from thiocolchicine with Raney nicel in aerial atmosphere was contamination with 1-2% thiocolchicine.

Animals↗
PubMed1986

Precursors of the mammalian synthesis of morphine: (+)-salutaridine and (-)-thebaine from (+)-6-demethylsalutaridine, and (-)-N-13CH3-thebaine from (-)-northebaine.

Standard samples of pure (+)-salutaridine and (-)-thebaine required to study the mammalian origin of morphine, were prepared from (+)-6-demethylsalutaridine by published procedures and were characterized by CD spectra and physical data. Reductive N-methylation of (-)-northebaine afforded (-)-thebaine, and when 13C-labeled formalin was used, (-)-thebaine with a 13C label on the N-methyl carbon atom resulted. The latter represents a model procedure to prepare ultimately N-14CH3-labeled (-)-thebaine and 14C-labeled congeners.

Animals↗