Alberto Bonsignori

Reboxetine: a pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor

BACKGROUND Reboxetine is a potent antidepressant, with efficacy comparable to that of imipramine, desipramine, and fluoxetine, and has improved side-effect profile. The basis of its efficacy and improved tolerability is sought through studies of reboxetine in a number of pharmacological models of depression. METHODS Pharmacological selectivity for uptake systems was defined by uptake and binding assays for the three monoamine uptake sites. Specificity was determined in 39 different receptor and 6 enzyme assays. In vivo selectivity was defined by measurement of neuronal firing rates in the locus coeruleus, dorsal raphe, and substantia nigra. Reserpine-induced blepharospasm and hypothermia, clonidine-induced hypothermia, defined reboxetines in vivo pharmacology. Reboxetines antidepressant potential was evaluated behaviorally by the tail-suspension test, forced swimming, and the DRL72 operant responding test. RESULTS Reboxetine is a potent, selective, and specific norepinephrine reuptake inhibitor (selective NRI) as determined by both in vitro and in vivo measurements. Unlike desipramine or imipramine, reboxetine has weak affinity (Ki > 1,000 nmol/L)for muscarinic, histaminergic H1, adrenergic alpha1, and dopaminergic D2 receptors. In vivo action of reboxetine is entirely consistent with the pharmacological action of an antidepressant with preferential action at the norepinephrine reuptake site. Reboxetine showed an antidepressant profile in all tests of antidepressant activity used. Significant decreases in immobility were observed in the tail suspension test and behavioral despair test. Increased efficiency in responding was observed in the DRL72 test. CONCLUSIONS Reboxetine is a potent, selective, and specific noradrenergic reuptake inhibitor. It has a superior pharmacological selectivity to existing tricyclic antidepressants and selective serotonin reuptake inhibitors when tested in a large number of in vitro and in vivo systems. Given the pharmacological profile, reboxetine is expected to be a selective and potent tool for psychopharmacological research. The use of reboxetine in the clinic will also help clarify the role norepinephrine plays in depression.

Is the oxidation of milacemide by monoamine oxidase a major factor in its anticonvulsant actions

The anticonvulsant drug milacemide (2-n-pentylaminoacetamide) is known to be oxidized by monoamine oxidase-B to yield glycinamide which then breaks-down to give glycine. It has been postulated that it is this liberation of glycine in the brain that accounts for the anticonvulsant effects. In order to test this hypothesis, and since amines bearing a methyl-group in the alpha-position have been shown to be resistant to oxidation by monoamine oxidase, the effects of milacemide were compared with those of alpha-methyl-milacemide. Although the latter compound was found to be toxic at higher concentrations, it was found to antagonize bicuculline-induced convulsions in mice. When milacemide was administered to mice (0.5 mmol/kg, p.o.) there was a substantial increase in urinary glycinamide excretion. No such increase was observed after the administration of the same dose of alpha-methyl-milacemide. Furthermore, alpha-methyl-milacemide was not oxidized by either monoamine oxidase-A or -B in vitro to any detectable extent, although it was a competitive inhibitor of both forms of the enzyme. The findings that alpha-methyl-milacemide has anticonvulsant properties in the bicuculline test but is not a substrate for monoamine oxidase or a source of urinary glycinamide cast doubt on the importance of the oxidation or milacemide to form glycinamide as a major factor in its anticonvulsant action.

Sodium channel activity and sigma binding of 2-aminopropanamide anticonvulsants.

Sodium channel blocking, anticonvulsant activity, and sigma (sigma) binding of selected leads in a series of alpha-amino amide anticonvulsants were examined. While anticonvulsant compounds were always endowed with low micromolar sodium (Na+) channel site-2 binding, compounds with low site-2 Na+ channel affinity failed to control seizures. No correlation could be drawn with sigma1 binding. Both anticonvulsant and Na+ channel blocking activities were independent of stereochemistry, while sigma1 binding seems to be favoured by an S-configuration on the aminoamide moiety.

MAO activity, metabolism and anticonvulsant activity of milacemide in rats and mice

Milacemide was found to protect Swiss albino CD1 mice but not Sprague Dawley rats against bicuculline-induced lethality. Since it had been previously suggested that the anticonvulsant activity of milacemide might be related to MAO-B- mediated glycine formation, brain and liver MAO-A and-B activities and the urinary metabolic pattern of milacemide were determined in the same mice and rat strains. Similar brain and liver MAO activities were found in the two species, except for liver MAO-A activity which was higher in rats. After the same oral dose of milacemide, the percent of the dose excreted as glycinamide was significantly higher in mice than in rats, whereas that excreted as metabolite UK1 was significantly higher in rats. These results support the hypothesis of a glycine-mediated anticonvulsant activity for milacemide and suggest that the increased formation of UK1 to the detriment of glycinamide might account for the lack of protection against bicuculline-induced lethality by milacemide in rats.

Synthesis and preliminary biological evaluation of new α-amino amide anticonvulsants incorporating a dextromethorphan moiety

Dextromethorphan 1 is an effective neuroprotectant in animal models of epilepsy and ischemia but showed side-effects during clinical trials limiting its potential use in a clinical setting. Here we describe the enantioselective and enantiospecific syntheses and the initial in vitro and in vivo biological evaluation of new hybrid structures between 1 and a previously disclosed alpha-amino amide anticonvulsant (3).

Synthesis of new fenmetazole analogues with potential mixed α2-adrenergic antagonistic activity and noradrenaline-uptake inhibiting properties

Abstract In the search for new antidepressants with a rapid onset of action, fenmetazole analogues, bearing a second phenyl ring in a position previously shown not to be detrimental to affinity and selectivity for the α 2 -adrenoreceptors, were synthesized in an attempt to combine NA-uptake inhibition and blockade of the α 2 -adrenoreceptors in the same molecule. Some of the new molecules showed enhanced affinity and selectivity for the α 2 -adrenoreceptors compared to fenmetazole. Surprisingly, introduction of a phenyl ring in the structure of fenmetazole changed the agonistic action of the parent compound toward the α 1 -adrenoreceptors into an antagonistic effect. However, none of the new derivatives showed in vitro NA-uptake inhibitory potency substantially different from the low activity of fenmetazole in this test.

Research of potential antidepressant drugs with α2-adrenoreceptor antagonist and NA-uptake inhibiting properties: synthesis of 2-(1-hydroxy-2-phenoxy-2-phenyl)ethyl-4,5-dihydro-1H-imidazole derivatives

Abstract A series of 2-(1-hydroxy-2-phenoxy-2-phenyl)ethyl-4,5-dihydro-1 H -imidazole derivatives has been synthesized with the aim of finding potential antidepressant drugs endowed with both NA-uptake and α 2 -antagonist properties. The structure of the new compounds was designed by mixing the common elements present in reboxetine and α-aryloxy-benzyl derivatives of ethanolamine, both having NA-uptake inhibitory properties in vitro , and in idazoxan, a potent and selective α 2 -adrenoreceptor antagonist. The new hybrids allow a good fitting of the common features without the strong steric interactions occurring when the structure of reboxetine is superimposed on that of idazoxan. However, the new derivatives did not display significant interaction with the NA-uptake system and the α 2 -adrenoreceptors and proved inactive in the antireserpine test taken as a model of potential antidepressant activity. The possible relationship between the structural changes made in the parent molecules and the complete loss of activity on both systems is discussed.