ABSTRACT
The goal of retrometabolic drug design is: "to design safe, locally active compounds with an improved therapeutic index". Here we describe two cases from our own practice, talampanel and omeprazole.
Subject(s)
Anticonvulsants/chemical synthesis , Anticonvulsants/metabolism , Benzodiazepines/chemical synthesis , Benzodiazepines/metabolism , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Omeprazole/chemical synthesis , Omeprazole/metabolism , Anticonvulsants/pharmacology , Benzodiazepines/pharmacology , Enzyme Inhibitors/pharmacology , Indicators and Reagents , Omeprazole/pharmacology , Proton Pump Inhibitors , Structure-Activity RelationshipABSTRACT
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/pharmacologyABSTRACT
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 RelationshipABSTRACT
Over the past 20 years, several members of the 2,3-benzodiazepine family have been synthesized. Some of these compounds--tofisopam (Grandaxin), girisopam, nerisopam--exert significant anxiolytic and antipsychotic activities. Sites where actions of 2,3-benzodiazepines are mediated differ from those of 1,4-benzodiazepines. Binding of 2,3-benzodiazepines to neuronal cells in the central nervous system shows a unique and specific distribution pattern: their binding sites are located exclusively to the basal ganglia. Chemical lesioning of the striato-pallido-nigral system, surgical transections of the striato nigral pathway and the activation of c-fos expression in the basal ganglia after application of 2,3-benzodiazepines suggest that these compounds mainly bind to projecting neurons of the striatum. The binding sites are transported from the striatum to the substantia nigra and the entopeduncular nucleus. Recent studies on mechanism of action of 2,3-benzodiazepines indicate their possible role in opioid signal transduction since 2,3-benzodiazepines augment the agonist potency of morphine to induce catalepsy and analgesia, and their action is diminished in morphine tolerant animals. The possible biochemical target of 2,3-benzodiazepines is an alteration in the phosphorylation of protein(s) important in the signal transduction process. Agents affecting emotional responses evoked by endogenous opioids without danger of tolerance and dependence may represent a new therapeutic tool in the treatment of addiction and affective disorders.
Subject(s)
Anti-Anxiety Agents/pharmacokinetics , Basal Ganglia/drug effects , Benzodiazepines/pharmacokinetics , Binding Sites/drug effects , Excitatory Amino Acid Antagonists/pharmacokinetics , Animals , HumansABSTRACT
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 StrainsABSTRACT
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.
