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2.
Pharmazie ; 56 Suppl 1: S31-3, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11686088

ABSTRACT

The development of therapeutic agents against peptic ulcer at the Institute for Drug Research at Budapest is reviewed. Among others, the genesis of the omeprazole molecule is described.


Subject(s)
Anti-Ulcer Agents/chemical synthesis , Animals , Anti-Ulcer Agents/pharmacology , Gastric Acid/metabolism , Histamine/physiology , Humans , Hungary , Proton Pump Inhibitors
3.
Acta Pharm Hung ; 71(1): 40-3, 2001.
Article in Hungarian | MEDLINE | ID: mdl-11769095

ABSTRACT

2-Pyridyl-thioacetamide (2-PTA) was synthesized at IDR in 1968. This molecule showed strong antiulcer/antisecretory effects in animals and man by inhibiting the proton pump. Based on our work Astra developed omeprazole which is the No. 1 drug in the world from 1996. 2-PTA remained a very popular template for drug design for a quarter of century.


Subject(s)
Anti-Ulcer Agents/pharmacology , Academies and Institutes , Anti-Ulcer Agents/chemical synthesis , Anti-Ulcer Agents/therapeutic use , Humans , Hungary , Peptic Ulcer/drug therapy , Research/trends
4.
Bioorg Med Chem ; 8(8): 2127-43, 2000 Aug.
Article in English | MEDLINE | ID: mdl-11003158

ABSTRACT

New halogen atom substituted 2,3-benzodiazepine derivatives condensed with an azole ring on the seven membered part of the ring system of type 3 and 4 as well as 5 and 6 were synthesized. It was found that chloro-, dichloro- and bromo-substitutions in the benzene ring and additionally imidazole ring condensation on the diazepine ring can successfully substitute the methylenedioxy group in the well known molecules GYKI 52466 (1) and GYKI 53773 (2) and the 3-acetyl-4-methyl structural feature in 2, respectively, preserving the highly active AMPA antagonist characteristic of the original molecules. From the most active compounds (3b,i) 3b (GYKI 47261) was chosen for detailed investigations. 3b revealed an excellent, broad spectrum anticonvulsant activity against seizures evoked by electroshock and different chemoconvulsive agents indicating a possible antiepileptic efficacy. 3b was found to be highly active in a transient model of focal ischemia predictive of a therapeutic value in human stroke. 3b also reversed the dopamine depleting effect of MPTP and antagonized the oxotremorine induced tremor in mice indicating a potential antiparkinson activity.


Subject(s)
Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacology , Receptors, AMPA/antagonists & inhibitors , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/antagonists & inhibitors , Animals , Anti-Anxiety Agents/chemistry , Anticonvulsants/chemistry , Benzodiazepines/chemistry , Disease Models, Animal , Drug Design , Humans , Kainic Acid/antagonists & inhibitors , Kainic Acid/pharmacology , Male , Mice , Molecular Structure , Muscarinic Agonists/pharmacology , Oxotremorine/pharmacology , Patch-Clamp Techniques , Purkinje Cells/drug effects , Purkinje Cells/metabolism , Rats , Retina/drug effects , Retina/physiology , Seizures/chemically induced , Structure-Activity Relationship , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology
5.
Bioorg Med Chem Lett ; 10(9): 899-902, 2000 May 01.
Article in English | MEDLINE | ID: mdl-10853655

ABSTRACT

Some 5-methyl analogues (14a-e) of the non-competitive AMPA antagonists 3-acylated 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-4,5-dihydro-3H-2,3-benzodi azepines (2,3) have been synthesized. Generally they show diminished or low biological activity but two derivatives (14a,b) reveal effects comparable to those of GYKI 52466 (1), the prototype non competitive AMPA antagonist.


Subject(s)
Azepines/chemical synthesis , Benzodiazepines , Receptors, AMPA/antagonists & inhibitors , Animals , Anti-Anxiety Agents/pharmacology , Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Azepines/pharmacology , Behavior, Animal/drug effects , Brain Ischemia/drug therapy , Cells, Cultured , Chickens , Electroshock , Humans , Mice , Patch-Clamp Techniques , Purkinje Cells/drug effects , Rats , Retina/drug effects , Structure-Activity Relationship
6.
Acta Physiol Hung ; 79(2): 153-61, 1992.
Article in English | MEDLINE | ID: mdl-1363928

ABSTRACT

The anxiolytic action of two 2,3-benzodiazepines: girisopam: GYKI 51,189 (EGIS 5810): (1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine), and GYKI 52,322 (EGIS 6775): (1-(4-aminophenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine) was investigated in comparison to chlordiazepoxide and buspirone using three different animal models of anxiety: the lick conflict, the elevated plus maze and the open field methods in rats. Both 2,3-benzodiazepines exerted anxiolytic effect in all three tests used, however their pharmacological profile differs considerably from that of either chlordiazepoxide or buspirone. Using the animal models mentioned above the order of potency was GYKI 52,322 (EGIS 6775) > chlordiazepoxide > girisopam > buspirone.


Subject(s)
Anti-Anxiety Agents/pharmacology , Benzodiazepines/pharmacology , Buspirone/pharmacology , Chlordiazepoxide/pharmacology , Animals , Conflict, Psychological , Dose-Response Relationship, Drug , Electroshock , Exploratory Behavior/drug effects , Male , Rats , Rats, Inbred Strains
7.
Acta Physiol Hung ; 79(2): 163-9, 1992.
Article in English | MEDLINE | ID: mdl-1363929

ABSTRACT

GYKI 52466 is a specific antagonist of the neuronal excitation mediated by the non-NMDA type excitatory amino acid receptors, at several sites in the central nervous system. The experiments presented here show that the drug has a dose-dependent, slowly developing, long-lasting and reversible inhibitory action on the field potentials recorded from the CA1 region of the rat hippocampus, in vitro. Its action is similar to that of the well-known non-NMDA receptor blocker, CNQX. When the stimulus intensity-dependence of the population spikes was investigated, both drugs shifted the input-output curves in a parallel manner, while the maximum responses were only slightly depressed at the doses applied. With i.v. application, GYKI 52466 also inhibited the hippocampal field potentials recorded from the CA1 region of anesthetized rats dose-dependently. The inhibition was relatively weak compared to the effect found in earlier studies in the spinal cord, by the same doses. Four mg/kg i.v., a doses which is able to block spinal reflexes completely, caused an only about 20% depression of the recorded responses in the hippocampal CA1 area.


Subject(s)
Anti-Anxiety Agents/pharmacology , Benzodiazepines/pharmacology , Hippocampus/drug effects , 6-Cyano-7-nitroquinoxaline-2,3-dione , Animals , Depression, Chemical , In Vitro Techniques , Male , Membrane Potentials/drug effects , Quinoxalines/pharmacology , Rats , Rats, Sprague-Dawley , Stereotaxic Techniques
9.
Arzneimittelforschung ; 39(8): 894-9, 1989 Aug.
Article in English | MEDLINE | ID: mdl-2573361

ABSTRACT

The neuropharmacological effects of 1-(4-amino-phenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (GYKI 52 322) were investigated and compared with those of chlordiazepoxide and chlorpromazine. This novel 2,3-benzodiazepine displays neuroleptic activity in the apomorphine-climbing (ED50 = 1.15 mg/kg i.p.) and swim-induced grooming (ED50 = 6.9 mg/kg i.p.) tests in mice and it inhibits the conditioned avoidance response in rats (ED50 = 8.2 mg/kg i.p. and 9.8 mg/kg p.o.). However, it does not antagonize apomorphine-evoked vomiting in dogs; or stereotypy, hypermotility and turning in rats even at as high a dose as 50 mg/kg i.p. On the other hand it is active in the hole board test in mice (MED (minimal effective dose) = 0.5 mg/kg i.p.) and in the lick conflict assay in rats (MED = 5 mg/kg i.p.), indicating anxiolytic property. It shows antiaggressive effect in the fighting mice test (ED50 = 8.1 mg/kg p.o.) and the carbachol-rage procedure in cats (active at 10 mg/kg i.p.) According to the biochemical findings, this compound does not bind to the central dopamine receptors (IC50 greater than 10(-4) mol/l), but it shows affinity to the 5-HT1 receptors (IC50 = 7.1 x 10(-6) mol/l) and inhibits brain cAMP-phosphodiesterase (IC50 = 2.4 x 10(-5) mol/l). The substance causes no elevation of dopamine turnover and serum prolactin level suggesting fewer side effects. So the term "atypical neuroleptic agent" is proposed to characterize this molecule.


Subject(s)
Anti-Anxiety Agents/pharmacology , Behavior, Animal/drug effects , Benzodiazepines/pharmacology , Adenylyl Cyclases/metabolism , Aggression/drug effects , Animals , Anti-Anxiety Agents/toxicity , Antipsychotic Agents , Benzodiazepines/toxicity , Brain/enzymology , Brain Chemistry/drug effects , Catalepsy/chemically induced , Cats , Conflict, Psychological , Electroencephalography , Female , Grooming/drug effects , In Vitro Techniques , Male , Mice , Molecular Weight , Prolactin/blood , Rats , Substance-Related Disorders/psychology
10.
Eur J Pharmacol ; 167(2): 193-9, 1989 Aug 22.
Article in English | MEDLINE | ID: mdl-2574112

ABSTRACT

The effects of GYKI 52466, a new 2,3-benzodiazepine with muscle relaxant and anticonvulsant properties, were investigated and compared to those of midazolam in electrophysiological experiments. The effects of the drugs on the reflex potentials evoked by afferent nerve stimulation and recorded from the spinal roots in unanesthetized spinal cats were studied. GYKI 52466 exerted a strong inhibitory effect on the monosynaptic as well as the polysynaptic ventral root reflexes, while the dorsal root responses decreased slightly. In contrast, midazolam markedly enhanced the dorsal root responses, did not modify the monosynaptic reflex and partially inhibited the polysynaptic reflex. The spontaneous firing of cerebellar Purkinje cells was depressed by midazolam, but not by GYKI 52466. These results suggest strongly that, contrary to the classical 1,4-benzodiazepines, potentiation of the GABA-A receptor-mediated inhibition does not play a significant role in the pharmacological actions of GYKI 52466.


Subject(s)
Anti-Anxiety Agents/pharmacology , Benzodiazepines/pharmacology , Muscle Relaxants, Central/pharmacology , Animals , Cats , Electrophysiology , Evoked Potentials/drug effects , Male , Midazolam/pharmacology , Purkinje Cells/drug effects , Purkinje Cells/metabolism , Receptors, GABA-A/drug effects , Receptors, GABA-A/metabolism , Reflex, Monosynaptic/drug effects , Spinal Cord/drug effects , Spinal Cord/metabolism , Spinal Cord/physiology
11.
Pharmazie ; 44(3): 191-3, 1989 Mar.
Article in English | MEDLINE | ID: mdl-2748704

ABSTRACT

4-(3-Pyridyl)thiazole and 2-methylimidazo[1,2-a]pyridine derivatives with anticholinergic antisecretory activity were synthesized. Most of the compounds (3-16) were formed from carbohydrazide 2 and carbonitrile 9. Some thiazole derivatives, most of them containing nitrogen attached to the thiazole C-2 (19-20), were prepared from 17 and 18 by known method. Compounds 12 and 19b exerted a significant antisecretory whereas 5b, 12 and 19b an antiulcer activity.


Subject(s)
Anti-Ulcer Agents/chemical synthesis , Gastric Acid/metabolism , Pyridines/chemical synthesis , Thiazoles/chemical synthesis , Animals , Chemical Phenomena , Chemistry, Physical , Female , Pyridines/pharmacology , Rats , Spectrophotometry, Infrared , Thiazoles/pharmacology
12.
Arzneimittelforschung ; 37(10): 1119-24, 1987 Oct.
Article in English | MEDLINE | ID: mdl-2893623

ABSTRACT

1-(3-Chlorophenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (GYKI 51189) is a new analogue of tofisopam. Due to the novel chemical structure this molecule displays a peculiar spectrum of pharmacological activity. In many respects tofisopam and its new analogue differ from the traditional 1,4-benzodiazepines, e.g. in that they possess selective anxiolytic action without muscle relaxant and anticonvulsive activity, as well as they do not show any affinity for the 1,4-benzodiazepine receptors. This new compound exerts more pronounced anxiolytic potency than tofisopam. In addition to its main action it possesses significant antidepressant activity. It attenuates psychomotor agitation and exerts significant antiaggressive effect by reducing both spontaneous and induced aggressiveness. Vegetative responses (rise in blood pressure and heart rate) induced by electric stimulation of the hypothalamus are also inhibited by this compound, while motor functions remain unaffected and no somnolence is induced. The new tofisopam analogue fails to exert any potentiating effect either on ethanol or on barbiturates. GYKI-51189 has a highly favourable therapeutic index and only few side effects. Neither tolerance nor dependence was observed during the chronic toxicological investigations.


Subject(s)
Anti-Anxiety Agents/pharmacology , Benzodiazepines/pharmacology , Aggression/drug effects , Animals , Anti-Anxiety Agents/toxicity , Anticonvulsants , Antidepressive Agents , Benzodiazepines/toxicity , Brain Chemistry/drug effects , Cats , Electroencephalography , Female , Hexobarbital/pharmacology , Male , Mice , Motor Activity/drug effects , Psychomotor Performance/drug effects , Rats , Sleep/drug effects , Species Specificity , Time Factors
13.
Eur J Pharmacol ; 80(4): 359-68, 1982 Jun 04.
Article in English | MEDLINE | ID: mdl-6125401

ABSTRACT

Several conventionally used in vivo pharmacological assays were applied to examine whether morphine (M) and a potent enkephalin analogue, [D-Met2,Pro5]enkephalinamide (DMPEA) have haloperidol (H)-like neuroleptic activity. The apomorphine (A)-induced stereotypy and the conditioned reflex activity were inhibited by extremely low doses of H, while somewhat higher doses were needed to induce catalepsy or to suppress the A-elicited turning behaviour in rats with unilateral nigral lesion. M produced these effects only in doses higher than needed for analgesia. DMPEA, however, attenuated the A-elicited stereotypy already at a subanalgesic dose level but it was very weak in the other tests. Furthermore, neither M nor DMPEA inhibited the A-elicited stereotypy completely. Consequently, these drugs exhibit strikingly dissimilar relative potencies in the in vivo assays considered specific for neuroleptics. Our findings, in accordance with much of the data available, suggest that neither M nor DMPEA has a specific neuroleptic activity.


Subject(s)
Antipsychotic Agents/pharmacology , Endorphins/pharmacology , Enkephalin, Methionine/analogs & derivatives , Enkephalins/pharmacology , Morphine/pharmacology , Animals , Apomorphine/pharmacology , Conditioning, Classical/drug effects , Dose-Response Relationship, Drug , Haloperidol/pharmacology , Humans , Male , Motor Activity/drug effects , Rats , Rats, Inbred Strains , Rotation , Stereotyped Behavior/drug effects
14.
Acta Physiol Acad Sci Hung ; 47(4): 323-33, 1976.
Article in English | MEDLINE | ID: mdl-203165

ABSTRACT

The present state of chemistry, structure-activity relationship and cellular mode of action of gastrointestinal polypeptide hormones (gastrin, secretin, cholecystokinin-pancreozymin, caerulein and bombesin) are reviewed. Possible structure of polypeptide receptors and the mechanism of peptide--receptor interaction are described, and the role of acetylcholine and histamine in secretion discussed. The present data support the hormonal-receptor significance of cyclic nucleotides (cAMP, cGMP) in the cellular regulation of secretion.


Subject(s)
Gastrointestinal Hormones/pharmacology , Amino Acid Sequence , Animals , Anura , Bombesin/metabolism , Ceruletide/metabolism , Cholecystokinin/pharmacology , Gastrins/pharmacology , Glucagon/metabolism , Histamine/metabolism , Humans , Molecular Conformation , Rats , Receptors, Cell Surface/metabolism , Secretin/pharmacology , Structure-Activity Relationship , Swine
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