Omeprazole and talampanel as two examples of retrometabolic drug design.

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.

New non competitive AMPA antagonists.

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.

Structural analogues of some highly active non-competitive AMPA antagonists.

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.

Anxiolytic homophthalazines increase Fos-like immunoreactivity in selected brain areas of the rat.

Nerisopam, an anxiolytic and antipsychotic homophthalazine induces rapid, intense expression of Fos-like immunoreactivity in the rostral, dorsomedial and lateral parts of the striatum in the rat. Fos-positive cells also occurred in the globus pallidus, the olfactory tubercle and in the accumbens nucleus (in the cone and shell portions) but the substantia nigra, the entopeduncular and the subthalamic nuclei were virtually Fos-negative. 5 h after nerisopam application, however, cells in the reticular zone of the substantia nigra showed Fos-like immunopositivity. After a daily application of nerisopam for two weeks, relatively weak Fos-like immunoreactivity was observed in the striatum and the subthalamic nucleus but not in the globus pallidus. Unilateral surgical transection of the striato-nigral pathway, which depleted tyrosine hydroxylase immunostaining in the ipsilateral striatum did not influence nerisopam-induced Fos-like immunoreactivity in the striatal neurons, either ipsi- or contralateral to the knife cut. Our results suggest that the striatal neurons are the primary targets of this anxiolytic and antipsychotic drug in the central nervous system.

A new psychoactive 5H-2,3-benzodiazepine with a unique spectrum of activity.

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.

Electrophysiological studies with a 2,3-benzodiazepine muscle relaxant: GYKI 52466.

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.

Effects of some centrally acting muscle relaxants on spinal root potentials: a comparative study.

The effects of intravenously administered mephenesin, tolperisone, baclofen, diazepam and midazolam on reflex activity were studied in unanesthetized spinal cats. Monosynaptic, as well as polysynaptic ventral root reflexes, the dorsal root potential and the dorsal root reflex were recorded simultaneously from L6-S1 segments. An analogue integrating method was developed for quantitative monitoring and recording ipsilateral spinal root potentials evoked by stimulation of the tibial nerve. Mephenesin (12.5-50 mg/kg) caused a significant and dose-dependent reduction in the polysynaptic and the dorsal root reflexes, slightly decreased the dorsal root potential but minimally affected the monosynaptic ventral root reflex. Tolperisone (2.5-10 mg/kg) dose-dependently inhibited both ventral root reflexes and the dorsal root reflex. It slightly prolonged the dorsal root potential without affecting the amplitude. Baclofen (0.5 mg/kg) abolished the monosynaptic reflex, partially inhibited the polysynaptic reflex, while dorsal root responses were less attenuated. Both benzodiazepines exerted similar actions, both qualitatively as well as quantitatively: the polysynaptic reflex was partially reduced while the monosynaptic reflex was not modified by diazepam or midazolam. Dorsal root responses were enhanced and the half-time of decay of the dorsal root potential was prolonged. Different patterns of action of muscle relaxants studied here are discussed in terms of their possible mechanisms of action. Profound depressant effects of mephenesin and tolperisone on the dorsal root reflex are in contrast to the small effect of both drugs on the dorsal root potential and might reflect their inhibition of spike-generating mechanisms. For a yet unknown reason, various spinal pathways are affected differentially by baclofen. In spinal cats, the reduction by benzodiazepines of the polysynaptic reflex may be related to the potentiation of some unidentified GABA-ergic inhibitory processes. The use of water-soluble midazolam, as a model compound instead of diazepam, is suggested because the usual organic solvents for diazepam may affect its action.

Neuropharmacology of a new psychotropic 2,3-benzodiazepine.

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.