Biomedical subjects

S Hosztafi

Publications and source records attributed to S Hosztafi.

16 recordsLinked to original sources

PubMed1998

Affinity profiles of novel delta-receptor selective benzofuran derivatives of non-peptide opioids.

Highly selective heterocyclic opioid ligands with potent delta-antagonist activity have been developed on the basis of the "message-address" concept. Using this strategy, benzofuran derivatives corresponding to the non-selective opioid antagonist, naloxone, and to the mu-opioid receptor selective agonists, oxymorphone and oxycodone, were synthesized. In vitro opioid receptor binding profiles and agonist/antagonist character of these compounds were determined in rat brain membrane preparations with highly selective radioligands. All three benzofuran derivatives displayed high affinities for the delta-opioid receptor, much less potency toward the mu-binding site, and were the least effective at the kappa-site. The results indicated that the addition of the bezofuran moiety to these fused ring opioids confers delta-receptor selectivity. The Na+ indices suggested a partial agonist character for oxymorphone- and oxycodone-benzofuran, and an antagonist character for naloxone-benzofuran. These compounds were capable of irreversible inhibition of opioid binding sites in a dose-dependent.

Animals↗

PubMed1997

New nepenthone and thevinone derivatives.

The diastereoselective reaction of thevinone (2a) and nepenthone (2c) and their dihydro derivatives (2b and d) with Grignard reagents afforded new N-substituted (20S)- and (20R)-phenyl-6,14-ethenomorphinan derivatives (6a-y). The Grignard reaction of the N-substituted-N-demethyl derivatives 4a-f and 4m-r with methylmagnesium iodide resulted in the (20R)-phenyl tertiary alcohols 5a-f and 5m-r, respectively, but the conversion of 4g-1 and that of the N-substituted-dihydrothevinone derivatives with phenylmagnesium bromide afforded the (20S)-phenyl derivatives 5g-l and 5s-y, respectively. The N-cyclopropylmethyl-, N-beta-phenylethyl-, and N-propyl derivatives were prepared by the 3-O-demethylation of compounds 5. For the synthesis of the N-allyl-, N-dimethylallyl-, and N-propargyl compounds 2a-d were reacted with the corresponding Grignard reagent, and treatment of the products with cyanogen bromide gave the cyanamides 8a-d. These latter compounds were transformed into 10a, b,d, whose alkylation led to the target derivatives 6d-f, j-l, p-r, and w-y. The biochemical investigation of these substances showed that the affinities to the delta-opioid receptors were high, but the selectivity was low. In two cases (6c and 11d) a mu-opioid receptor specificity was observed.

Animals↗

PubMed1997

The discovery of alkaloids.

This paper presents the history of the discovery of the first alkaloids. Isolation of alkaloids is connected with the study of the active principles of medicines of plant origin, for example opium and cinchona bark. Sertürner described morphine as a plant alkali and claimed that it was capable of neutralizing free acids yielding salts. The recognition of alkaloids as a new class of compounds was an important step at that time because of the dogmatic denial of the possible existence of plant bases. Isolation of alkaloids is a significant event from the point of view of chemistry, physiology and medicine. The discovery caused essential conceptual changes in chemistry. Priority claims with reference to the discovery of the alkaloids are also reviewed.

Alkaloids↗

PubMed1994

Dihydrocodeinone-hydrazone, dihydrocodeinone-oxime, naloxone-3-OMe-oxime, and clocinnamox fail to irreversibly inhibit opioid kappa receptor binding.

Previous work from our lab identified two subtypes of the opioid kappa receptor. Whereas the kappa1 receptor can be labeled by [3H]U69,593 (5 alpha,7 alpha,8 beta-(-)- N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl]-phenyl- benzeneacetamide), the kappa2 receptor can be labeled by [125I]OXY (6 beta-125iodo-3,14-dihydroxy-17-cyclopropylmethyl-4,5 alpha-epoxymorphinan). Other data demonstrate that [125I]IOXY, like [3H]bremazocine, labels two populations of kappa2 receptors in guinea pig brain: kappa2a and kappa2b binding sites. In the present study, we tested the hypothesis that certain dihydrocodeinone and oxicodone derivatives, which have been shown to irreversibly block low affinity [3H]naloxone binding sites, would also bind irreversibly to opioid kappa receptor subtypes. We also tested the novel irreversible mu receptor antagonist, clocinnamox (14 beta-(p-chlorocinnamoylamino)-7,8-dihydro-N-cyclopropylmethylno rmorphinone mesylate). Wash-resistant inhibition (WRI) assays were conducted to detect apparent irreversible inhibition. The proportion of WRI attributable to inhibition of receptor binding, termed receptor inhibition (RI), was calculated by the equation: RI = WRI (wash-resistant inhibition) - SI (supernatant inhibition or inhibition attributable to residual drug.) Dihydrocodeinone-hydrazone, dihydrocodeinone-oxime and naloxone-3-OMe-oxime failed to produce any wash-resistant inhibition of kappa receptor binding. In contrast, preincubating guinea pig membranes with 1 microM clocinnamox produced a substantial degree of wash-resistant inhibition (greater than 90%) at kappa1 and kappa2 binding sites. However, as indicated by supernatant inhibition values of 70% to 90%, there was a large amount of residual clocinnamox which remained despite the use of an extensive washing procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

[Synthesis and analytical characterization of dansyl derivatives of morphine-like substances].

Dansyl derivatives of morphine-like substances were prepared using dansyl-chloride in acetone in the presence of sodium hydrogen carbonate. The reaction was selective for the phenolic hydroxyl group and was also quantitative. The purity of crystalline dansyl derivatives was checked by thin layer chromatography. Their structure was confirmed by PMR and MS spectra. Characteristic chemical shifts and MS fragments of the new derivatives were determined. UV spectra of the parent compounds and the dansyl derivatives were recorded. It was found that the absorbance of dansyl derivatives at 286 nm increased four-fold and a new band appeared at 320 nm. Some thin-layer chromatographic systems were elaborated to detect and separate dansyl derivatives. HPLC studies were done using normal as well as reversed phase. Parent compounds and their dansyl derivatives were separated easily by HPLC.

Dansyl Compounds↗

PubMed1993

Synthesis and analgetic activity of nicotinic esters of morphine derivatives.

The synthesis of morphine nicotinates is described using nicotinyl chloride in the presence of pyridine. Isomorphine and isocodeine nicotinates were prepared from the corresponding morphine and codeine derivatives with nicotinic acid in the presence of triphenylphosphine and diethyl azodicarboxylate. Unexpectedly the reaction of 14-hydroxy-dihydromorphinone derivatives was anomalous, enolesters were formed. The analgetic activity of selected compounds was determined.

Analgesics, Opioid↗

PubMed1993

Binding properties of the pure opioid antagonist [3H](N-propyl)-noroxymorphone in rat brain membranes.

(-)[N-(propyl)-14-OH-dihydromorphinan-6-one] = (N-propyl)-noroxymorphone and its multiple tritiated form (molar activity: 126 Ci/mmol; 1 Ci = 37 GBq) was synthesized. According to our knowledge this specific radioactivity exceeds all of the commercially available [3H]opioid ligands. The ligand was found to be a pure opioid antagonist in receptor binding assays performed with rat brain membranes. Scatchard analysis of equilibrium binding isotherms revealed one high affinity (Kd approximately 4 nM) binding site. Reversibility, stereospecificity and opioid nature of the binding was confirmed by ligand binding experiments. Because of its antagonist character combined with high specific radioactivity the ligand might be a useful tool in characterizing and purifying opioid receptors.

Animals↗

PubMed1993

[Structure-activity relationship of synthetic and semisynthetic opioid agonists and antagonists].

This account presents the chemical structure-pharmacological activity relationships of semi-synthetic morphine and synthetic morphinan and benzomorphan derivatives. Substitution of nitrogen confers the analgesic or morphine antagonist activity. Opiate receptor selectivity of these compounds is also discussed. The importance of morphine agonists, and antagonists is mentioned with particular reference to the opiate receptor mapping.

Molecular Structure↗

PubMed1991

Irreversible blockade of the high and low affinity (3H) naloxone binding sites by C-6 derivatives of morphinane-6-ones.

C-6 derivatives--hydrazones, phenylhydrazones, dinitrophenylhydrazones, oximes and semicarbazones--of morphinane-6-ones were synthesized and their binding characteristics were studied on rat brain membranes. The dihydromorphinone and oxymorphone derivatives compete for the (3H)naloxone binding sites with high affinity, while the dihydrocodeinone and oxycodone derivatives are less potent. The affinity of the new compounds is decreased for the delta sites as compared to the parent ligands. The ligands bearing bulky substituents also bind with low affinity to the kappa sites. The modification decreased the Na(+)-index of compounds indicating their mixed agonist-antagonist character. The dihydromorphinone derivatives are all capable to block irreversibly the high affinity binding site of (3H)naloxone, whereas the dihydrocodeionone derivatives block irreversibly the low affinity site. A possible mechanism for the inhibition is suggested.

Affinity Labels↗

PubMed1989

Effects of precocene analogs on the nematode Caenorhabditis remanei (var. Bangaloreiensis). I. Structure/activity relations.

Precocenes (PI and PII) and 114 of their analogs (PAs) were synthetized and tested on C. remanei embryos for their precocene-like (P-like) activities resulting in unusual development at sublethal doses. The P-like activity was quantitated by plotting the probit of the percentage of the developmentally affected survivors against the (log) dose to obtain the EC plot and the half effective concentration (EC50). All five PAs (PI, PII, 7-ethoxy-PII, 7-(prop-2-ynyloxy)-PI, and 6-methoxy-7-(prop-2-ynyloxy)-PII) which exert both antiallatal activity in insects and P-like activity in nematodes are 7-alkoxy-substituted 2,2-dimethylchromenes. Both activities can be enhanced by an additional 6-MeO-substitution or by an asymmetric 6,7-dialkoxy-substitution, on condition that R-7 is longer than R-6. There are many more similarities than dissimilarities in the structural requirements needed for antiallatal and P-like activities. All but three nonantiallatal PAs effective in nematodes are 7-prop-2-ynyloxy-subsituted; two are symmetrically 6,7-disubstituted, and one is heterosubstituted (thio-PI). All PAs with antiallatal but without P-like activity are 7-monosubstituted with a relatively long alkoxy group. Certain substitutions favor antiallatal activity and others P-like activity. The severe nematocidal effect of 6,7-methylenedioxy-2,2-dimethylchromene (inert in insects) is not accompanied by P-like activity. The present findings lend some indirect support to the supposition that JH-producing cells and/or JH-dependent function(s) might exist in the nematodes.

Animals↗

PubMed1989

Effects of oxymorphazone in frogs: long lasting antinociception in vivo, and apparently irreversible binding in vitro.

Oxymorphazone (at doses of 50-200 mg/kg) was found to be a relatively weak antinociceptive drug in intact frog (Rana esculenta) when acetic acid was used as pain stimulus. Frogs remained analgesic for at least 48 hrs following oxymorphazone (200 mg/kg) administration. The ligand increased the latency of wiping reflex in spinal frogs too. These effects were blocked by naloxone. In equilibrium binding studies (3H)oxymorphazone had high affinity to the opioid receptors of frog brain and spinal cord as well (apparent Kd values were 8.9 and 10.6 nM, respectively). Kinetic experiments show that only 25% of the bound (3H)oxymorphazone is readily dissociable. Preincubation of the membranes with labeled oxymorphazone results in a washing resistant inhibition of the opioid binding sites. At least 70% of the (3H)oxymorphazone specific binding is apparently irreversible after reaction at 5 nM ligand concentration, and this can be enhanced by a higher concentration of tritiated ligand.

Analgesics↗

PubMed1989

The antiallatal effects on locusts and lethal effects on nematodes of synthetic precocene-1 derivatives differing at the carbon 7 position.

Fourteen precocene-1 (P1) derivatives differing at C-7 were synthetized and tested for their antiallatal activities on Locusta migratoria (in vitro and in vivo) and nematocidal effects on Caenorhaditis elegans. An outstanding antiallatal effect was produced by 7-propargyloxy-P1 in vitro. It caused an elevated rate of mortality when applied in vivo to locusts or nematodes. The antiallatal effect of 7-cyclopentyloxy-P1 was not accompanied by toxicity. Aralkyloxy substitution at C-7 eliminated the precocene activity.

Animals↗

PubMed1987

Synthesis and binding of 3H-oxymorphazone to rat brain membranes.

Oxymorphazone is a 14-hydroxydihydromorphinone derivative which contains a C-6 hydrazone group and hence could serve as an irreversible label for opioid receptors. 3H-oxymorphazone was synthesized by the reaction of 3H-oxymorphone with excess hydrazine. A specific radioactivity of 640 GBq/mmol (17,3 Ci/mmol) was achieved. Both the unlabelled compound and the tritiated ligand show high affinity to mu and kappa opiate receptor subtypes in rat brain membranes. Two binding sites were detected by equilibrium binding studies, with apparent Kd values of 0.62 nM and 28 nM. About 20% of the H-oxymorphazone specific binding is irreversible after reaction at 1 nM ligand concentration, and this can be enhanced by a higher concentration of tritiated ligand. No azine formation was detected. Preincubation of the membranes with unlabelled oxymorphazone resulted in an irreversible blockade of the high affinity 3H-naloxone binding sites.

Animals↗

PubMed1986

Preparation of [3H]-oxymorphazone and its binding to rat brain membranes.

Oxymorphazone is a 14-hydroxydihydromorphinone derivative which contains C-6 hydrazone group and hence could serve as an irreversible label for opioid receptors. 3H-oxymorphazone was synthesized by the reaction of 3H-oxymorphone with excess hydrazine, with 640 GBq/mmol specific radioactivity. Both the unlabelled compound and the tritiated ligand show high affinity to mu and kappa opiate receptor subtypes in rat brain membranes. Two binding sites were detected by equilibrium binding studies. About 60% of the 3H-oxymorphazone specific binding is irreversible at 10nM ligand concentration. Preincubation of the membranes with unlabelled oxymorphazone resulted in an irreversible blockade of the high affinity 3H-naloxone binding sites.

Animals↗

PubMedDate not supplied

Endogenous morphine.

This review surveys the discovery of endogenous alkaloids in mammals. The formation of morphine in mammalian brain was assumed in 1970. The existence of morphine was demonstrated by radioimmunoassay. Identification of morphine was performed by spectroscopic methods. The isolation of mammalian morphine raises the question of biosynthesis. Recently, it has been shown that the biosynthetic pathway is similar to that that exists in poppy.

Alkaloids↗

PubMedDate not supplied

Influence of spatial orientation of the C-6-OH group in ring C of morphine derivatives on opioid activity.

The effect of epimerization on agonist and antagonist activities of morphine and dihydromorphine, and those of their N-allyl, -propyl and -cyclopropylmethyl derivatives, were studied in rat tail flick, hot plate and mice hot plate and in isolated guinea-pig ileum assays, respectively. Using the rat tail flick, hot plate and mice hot plate tests, isomorphine and dihydroisomorphine were observed to produce dose-dependent, naloxone-reversible agonist (antinociceptive) actions, in a similar dose range as their parent molecules (relative potencies: 0.6-1.9). Also, these compounds produced agonist activities in isolated tissue preparations in a naloxone-reversible manner. While the N-substituted derivatives of isomorphine and dihydroisomorphine failed to produce antinociceptive activities in the rat tail flick test, they proved to be strong agonists in the guinea-pig ileum experiments, although the Ke values of naloxone were 5-6 times higher against these compounds than against their N-CH3 counterparts. Both the agonist and antagonist activities of the N-cyclopropylmethyl derivatives were found to be most potent in the guinea-pig ileum. The epimerization of morphine and dihydromorphine and their N-substituted derivatives evoked only slight changes in opioid activities in vitro. In vivo, merely the allyl substitution on nitrogen influenced the antagonist activities of epimer pairs. In contrast, substantial changes in opioid profile were observed when N-methyl was replaced by allyl-, propyl- or cyclopropylmethyl. Changes performed this way evoked, on the one hand, an enhancement of the affinities of compounds to mu-receptors, with simultaneous loss of intrinsic efficacy at these receptors, and, on the other hand, promoted the appearance of an agonist profile on a distinct (kappa) opioid receptor.

Analgesia↗