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Biomedical subjects

G Tóth

Publications and source records attributed to G Tóth.

At least 91 records · Page 5Linked to original sources
PubMed1997

Synthesis of gonadotropin-releasing hormone III analogs. Structure-antitumor activity relationships.

Following the observation that the activity of gonadotropin-releasing hormone III (GnRH-III) in the suppression of growth of MDA-MB-231 and MCF-7 breast cancer cells surpasses that of GnRH and other analogs thereof, analogs of GnRH-III were synthesized to investigate the structural basis for the improved antitumor activity. Compounds synthesized include analogs with changes in the central sequence in which GnRH-III differs from GnRH and in the C- and N-terminal regions. The results indicate that a salt bridge between Asp6 and Lys8 stabilizes the active conformation of GnRH-III and show the importance of the Trp7. Replacement of the C-terminal Gly-NH2 with D-Ala-NH2 was not well tolerated, but replacement with ethylamide was. Replacement of pGlu1 with Ac-D-Trp appears to have a significantly deleterious effect on a unique conformation of GnRH-III which is responsible for its binding to the receptors on cancer cell lines and the resultant antitumor activity.

Antineoplastic Agents↗
PubMed1997

Met5-enkephalin-Arg6-Phe7, an endogenous neuropeptide, binds to multiple opioid and nonopioid sites in rat brain.

Receptor binding properties of the naturally occurring opioid heptapeptide MERF were studied in rat brain membrane preparations using tritium-labeled derivative of the peptide with 40 Ci/mmol specific radioactivity. Binding assays were performed in the presence of broad-spectrum peptidase inhibitors at 0 degree C. Under these conditions, the equilibrium binding was achieved in 30-40 min, and approximately 90% of the applied radioligand remained unchanged as determined by HPLC analysis. The apparent affinity (Kd value) of [3H]Met-enkephalin-Arg6-Phe7, calculated from saturation binding data, was 10.2 +/- 2.5 nM, and the maximal number (Bmax) of the heptapeptide binding sites was found to be 468 +/- 43 fmol/mg protein. About half the sites represent nonopioid sites because the Bmax was only 255 +/- 30 fmol/mg, when the nonspecific binding was measured with 1 microM naloxone. The rank order potencies of the examined compounds revealed that the opioid component of [3H]Met-enkephalin-Arg6-Phe7 recognition site are probably not mu and certainly not kappa 1 sites, whereas these sites are characterized by a kappa 2-like binding profile. Considering the discrepancies between rat and frog brain found in the affinity of some compounds, including naltrindole and norbinaltorphimine, the presence of a novel, MERF-selective "heptapeptide" binding site in rat brain membranes is also suggested. A number of the heterologous competition curves could be described by a high-affinity stereospecific component and a substantially lower-affinity binding element, which could completely be displaced with several peptide ligands such as Met5-enkephalin, dynorphin(1-13), and unlabeled MERF but not by other compounds such as [D-Ala2-(Me)Phe4-Gly5-ol]enkephalin, morphine, or naloxone. [3H]Met-enkephalin-Arg6-Phe7 binding can also be inhibited by FMRF-amide analogs and sigma receptor ligands, such as (+)N-allyl-normetazocine and haloperidol, although with moderate affinity. It is concluded that the stereospecific high-affinity binding is of opioid in character, whereas the residual sites characterized with their lower affinity are naloxone-insensitive nonopioid sites.

Animals↗
PubMed1997

Conformationally constrained deltorphin analogs with 2-aminotetralin-2-carboxylic acid in position 3.

Two approaches to the design of very active and highly selective delta opioid peptides were used to obtain new deltorpin analogs with altered hydrophobic and stereoelectronic properties. Deltorphin I and II analogs were synthesized involving the substitution of Ile instead of Val at positions 5 and 6 in the address domain and 2-aminotetralin-2-carboxylic acid (Atc) instead of Phe in the message domain. The peptides were agonists in the subnanomolar range in the MVD assay and in the micromolar or higher range in the GPI assay, showing a very high selectivity for delta receptors. A very similar trend could be observed in radioreceptor binding assays in which selective tritiated opioid ligands were used. (R)- and (S)-Atc-deltoriphins exhibited similar Ki values in the binding assay, with almost complete loss of the stereospecificity of the binding. Conformational studies provided evidence for the little disturbance of the backbone conformational equilibrium when Phe3 is replaced by (S)- or (R)-Atc. The use of the Atc constraint gives additional evidence that, during its interaction with the delta receptor, the side chain of residue 3 adopts the trans conformation at chi 1.

Analgesics, Opioid↗
PubMed1997

Synthesis of vinca alkaloids and related compounds. Part 84. Sulfonamide derivatives of some vinca alkaloids with cardiovascular activity.

(+)-Vincamine (1) and (+)-vinpocetine (2) were chlorosulfonylated and the resulting sulfonyl chloride isomers (3-6) were transformed into sulfonamides (7-10). The ester group of sulfonamides was modified by selective hydrolysis and transesterification. Apovincaminol derivatives (14-16) were also prepared by reduction. In addition to the known cerebrovascular effects of the unsubstituted compounds (1,2) sulfonamides also show a significant peripheral vasodilator effect.

Animals↗
PubMed1997

Analysis of the role of delta opioid receptors in gastroprotection in the rat.

The effect of delta opioid agonists - [D-Ala2, D-Leu5]-enkephalin (DADLE), [D-Pen2, D-Pen5]-enkephalin (DPDPE) and deltorphin II - on acidified ethanol induced gastric mucosal lesions was studied in the rat compared with that of morphine. It was found that DADLE, DPDPE, deltorphin II and morphine exerted a dose-dependent inhibition on the mucosal lesions injected subcutaneously, their ID50 values were 0.037, 1.8, 3.5 and 0.35 micromoles/kg, respectively. Naltrindole (10 mg/kg sc.), the selective delta opioid receptor antagonist, inhibited the gastroprotective effect of DADLE, DPDPE and deltorphin II, but it failed to antagonise the effect of morphine. Our results suggest that 1. delta receptors are involved in opioid-mediated gastroprotection, 2. ethanol-induced gastric mucosal damage in the rat may be a quick, simple in vivo model for screening opioid delta receptor agonists and antagonists in the periphery.

Analgesics↗
PubMed1997

The effects of brain and C-type natriuretic peptides on corticotropin-releasing factor in brain of rats.

The central corticotropin-releasing factor (CRF)-ergic system plays a critical role in anxiety and other behavioral stress responses. It has been shown that atrial (ANP), brain (BNP) and C-type (CNP) natriuretic peptides exert anxiolytic-like effects in behavioral studies. Our previous findings demonstrated that various doses of centrally administered ANP selectively altered the CRF content in different brain areas. In the present study, CRF immunoreactivity was determined in hypothalamic and extrahypothalamic brain regions after central injection of BNP or CNP in rats. A high dose (400 ng) of BNP significantly increased the CRF-like immunoreactivity (CRF-LI) in the hypothalamus and amygdala, while only a tendency towards an increase was found in the hippocampus. In the hypothalamus, the CRF-LI decreased after a high dose (400 ng) of CNP. The CRF-LI increased in the basal forebrain after a low dose (100 ng) of CNP. These results suggest that CRF may be involved in the mediation of some neuroendocrine and behavioral responses to BNP and CNP.

Animals↗
PubMed1997

Synthesis and binding characteristics of the highly selective radiolabelled deltorphin analogues containing 2-aminotetralin-2-carboxylic acid in position 3.

Following the description of [3H]Ile5,6deltorphin II, when it was reported that changes in hydrophobicity at positions 5 and 6 give rise to analogues with increased delta-receptor affinity and selectivity, new conformationally restricted deltorphin analogues were designed. A synthetic amino acid, 2-aminotetralin-2-carboxylic acid (Atc), was introduced at position 3 instead of Phe in Ile5,6deltorphin I and II, and the resultant compounds were prepared in tritiated form. Opioid binding sites specific for [3H]S-Atc3,Ile5,6deltorphin I and [3H]R-Atc3,Ile5,6deltorphin II were characterized in rat brain membranes. Their binding was saturable, stereoselective and inhibited by delta-selective ligands with high potency. They labelled single class of opioid sites at 35 degrees C with high affinity (Kd approximately 0.3 nM), Bmax values of 130 fmol/mg protein, and very low non-specific binding was observed. Both tritiated deltorphin analogues showed delta-receptor specificity in rat brain, therefore they could represent excellent new radioligands for investigating the complexity of the opioid receptor systems.

2-Naphthylamine↗
PubMed1997

Synthesis and opioid binding activity of dermorphin analogues containing cyclic beta-amino acids.

In the present work, eight conformationally constrained analogues of the mu specific opioid peptide dermorphin were synthesized by replacing D-Ala2 with stereoisomers of beta-amino-cycloalkane or cycloalkene carboxylic acids. The resulting peptides were tested for their potency to mu and delta opioid binding sites of rat brain membranes labelled with [3H]Tyr1-D-Ala2-MePhe4-Gly-ol, [3H]DAMGO and [3H]Ile5,6deltorphin, respectively. All of the new derivatives displayed highly attenuated binding to both receptor types, albeit the decrease in their potency seemed to be less in the case of delta binding. Trans position of the beta-amino groups resulted in higher binding affinities than that of the corresponding cis isomers, the latter being more flexible than the former. It is concluded that conformational constraints caused either by a rigid ring structure or cis isomers instead of D-Ala2 in dermorphin-derived peptides are unfavourable for binding activity to either opioid receptors. We propose that interaction of the larger heptapeptide derivatives of dermorphins with the mu receptor is distinct from that of the tetrapeptide morphiceptin.

Amino Acids, Cyclic↗
PubMed1997

Site, histological type, and thickness of primary cutaneous malignant melanoma in western Netherlands since 1980.

An increasing incidence of cutaneous malignant melanoma had been observed in the Netherlands. Therefore, between 1989 and 1992 a preventive skin cancer campaign was organized in part of western Netherlands. The effect of this screening campaign has yet to be evaluated by investigating the distribution of all in situ and invasive primary cutaneous melanoma according to anatomical subsite, tumour thickness, and histological type in a population-based study during 1980-92. A total number of 2236 (1361 female; 875 male) invasive and 580 (395 female; 185 male) in situ melanomas were diagnosed. The median age of patients with thin lesions was 46 years, intermediate lesions 54 years, and thick lesions 65 years, which may be indicative of slow tumour progression. The median thickness of the invasive lesions was 0.9 mm for women and 1.1 mm for men and the invasive to in situ ratio was 3.4 for female and 4.7 for male subjects, suggesting a reasonable awareness of melanoma in this population. The relative tumour density (RTD) was remarkably high for melanomas in the head/neck area for both sexes and invasive melanoma on the male trunk and the lower legs of females. The low RTD of invasive melanomas on the lower limbs of men and the high density in the head/neck area for both sexes are remarkable and support the aetiological role of ultraviolet exposure. It is concluded that our findings are in many ways similar to those of other descriptive studies.

Adolescent↗
PubMed1997

Protection of the renal artery in nephron-sparing surgery. I. Pathomorphological study.

It is necessary to clamp the renal artery for some time in renal surgery to preserve the organ. Not only the renal parenchyma but also the wall of the clamped renal artery may be damaged due to known ischaemic-reperfusion causes. Regional venous renal hypothermia induced by intracellular solutions (Sacks II, Euro-Collins) could provide protection against damage of the vessel wall caused by reperfusion or clamping in our experiments, in cases of clamping for 30 minutes, probably because it also ensured the cooling of the surface of the vessel wall. Similar vasoprotective effect could be achieved by systematic antioxidant treatment (MTDQ-DS) and regional renal hypothermia given in combination. Harmful effects of 45-minute clamping could be best avoided by applying antioxidant treatment alone. While there were no significant morphological changes in the renal arteries the persistent endothelial damage may trigger further complications like renal ischaemic condition.

Animals↗
PubMed1997

Protection of the renal artery in nephron-sparing surgery. II. Arterial contractility investigations.

It has been well known that reperfusion following ischaemia may cause functional and structural damage to not only the organ involved but also the blood vessels supplying that organ. As in organ-sparing renal surgery it is inevitable to clamp the renal artery for some time, it is expected that reperfusion, following the removing of clamping, causes structural changes in the vessel wall which may result in a decrease in arterial function. In our model experiments on animals, the left renal arteries were atraumatically clamped for 30, 45 and 60 minutes. Simultaneously with clamping, perfusion regional renal venous cooling was applied to some of the animals, together with nephrotomy. In some cases cooling was performed in combination with antioxidant treatment. On the 3rd postoperative day renal arteries from both sides were removed, the right, intact ones serving as control. Noradrenaline dose effect curves characterizing vessel contractility were determined to demonstrate functional changes. It was established that cooling the renal artery for only 30 minutes was enough to rule out the damage due to ischaemia-reperfusion. If clamping lasted for 45 minutes, venous cooling of the kidney in combination with antioxidant treatment was necessary to spare arterial function. Clamping for 60 minutes resulted in irreversible/permanent decrease in contractility even if hypothermia and antioxidant treatment were given simultaneously.

Animals↗
PubMed1997

[Chemistry of A-2545, an anti-arrhythmia drug candidate. I. Structure elucidation of its main hydrolysis product].

A great number of antiarrhythmic agents with 2,2,5,5-tetramethyl-3-pyrroline (and pyrrolidine)-3-carboxamide structure were synthesized. One of them A-2545 (1) was selected for further investigation aiming the elucidation of its chemical properties. The hydrolysis of 1 was studied, where theoretically seven hydrolysis products might be formed (2-8, Fig.1.). The hydrolysis takes place in aqueous solution of 1. HCl also at room temperature. In alkali-catalyzed process only one main product can be detected by TLC. This hydrolysis product was assigned as phthalamide acid (2) proved by chromatographic, thermic, GC-MS and NMR methods. An interesting behaviour of 2 upon GC-MS investigation (thermic and electron impact) is its recyclisation to 1 at the injector temperature (140 degrees) thus 2 appears in the mass spectrum as it would be A-2545 (Fig. 2. and 3.).

Anti-Arrhythmia Agents↗
PubMed1996

Separation of enantiomeric beta-methyl amino acids and of beta-methyl amino acid containing peptides.

Erythro-D,L- and threo-D,L-beta-methylphenylalanine, -beta-methyltyrosine and -beta-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid were synthesized. High-performance liquid chromatographic methods were developed for the separation and identification of the enantiomers of the beta-methyl amino acids, with the application of 1-fluoro-2,4-dinitrophenyl-5-L-alanine amide and 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate as derivatizing reagents. These amino acids were incorporated into the mu-agonist/delta-antagonist opioid peptides H-beta-MeTyr-Tic-Phe-Phe-NH2, H-Tyr-Tic-beta-MePhe-Phe-NH2 and H-Tyr-Tic-Phe-beta-MePhe-NH2, and the delta-antagonist H-Tyr-beta-MeTic-Phe-Phe-OH, by solid-phase peptide synthesis. Each peptide has four stereoisomers. The peptide stereoisomers were separated on different columns and in different eluent systems and the elution order of the peptide epimers was determined.

Amino Acid Sequence↗
PubMed1996

The effects of atrial natriuretic peptide (ANP1-28) on corticotropin releasing factor in brain of rats.

We have shown that ANP has anxiolytic-like effects in behavioral studies. Since CRF is thought to be involved in emotional state of the brain, the present study was undertaken to follow the possible alterations in corticotropin-releasing factor-like immunoreactivity (CRF-LI) in different regions of the brain in rats following ANP treatment. CRF-LI immunoreactivity was determined in hypothalamic and extrahypothalamic brain areas after central injection of atrial natriuretic peptide 1-28 (ANP1-28) in rats. After various doses of ANP1-28 administration the CRF-LI significantly increased in the hypothalamus, the hippocampus and the frontal cortex. In the amygdala, ANP caused a marked but nonsignificant CRF-LI enhancement. In the basal forebrain, the CRF-LI decreased. These results suggest that ANP1-28 may moderate activation of the CRF-ergic system in the brain which could be related to the neuroendocrine and behavioral action.

Animals↗
PubMed1996

Effect of receptor blockers on brain natriuretic peptide and C-type natriuretic peptide caused anxiolytic state in rats.

Effect of different doses of centrally administered brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were examined in rats with respect to anxiolytic properties in an elevated plus-maze model. BNP in doses of 100, 200 and 400 ng, and CNP in doses of 100 and 200 ng abolished the normal preference for the closed arms of the maze, and increased the percentage time spent in the open arms; this is consistent with an 'anxiolytic-like' effect. Doses of 50 and 1000 ng BNP, and of 25, 50, 400 and 1000 ng CNP produced no behavioural effects in the elevated plus-maze model. Pretreatment with an alpha-adrenoreceptor antagonist or a muscarinergic cholinergic blocker, antagonized the effect of 200 ng BNP in the elevated plus-maze test. The 'anxiolytic-like' effects of a BNP were not modulated by a dopaminergic blocker, an alpha-adrenoreceptor antagonist, a GABA receptor antagonist, a 5-HT receptor antagonist or an opiate antagonist. The 'anxiolytic-like' effect of CNP was prevented by a dopamine receptor antagonist, or an alpha- or beta-adrenoreceptor blocker but not by a muscarinergic cholinergic blocker, a GABA receptor, a 5-HT receptor antagonist or an opiate receptor antagonist. These results suggest that multiple neurotransmitter system activation might be responsible for the BNP and CNP-induced 'anxiolytic-like' activity.

Animals↗
PubMed1996

The involvement of nitric oxide (NO) in the CGRP-induced behavior of rats.

The possible role of nitric oxide (NO) in CGRP-induced passive avoidance, active avoidance, and open field behavior was tested in rats. A specific NO synthase inhibitor, N omega-nitro-L-arginine (L-NA), was used to disrupt NO synthesis. ICV administration of 5 micrograms of L-NA reversed the action of CGRP in passive and active avoidance tests. In an open field, L-NA prevented the action of CGRP on locomotion and grooming. The inactive isomer D-NA had no effect on behavior of animals. The data suggest that NO might contribute to CGRP-induced behavior in rats.

Animals↗