Monoamine oxidase inhibitors were among the first antidepressants to be discovered and have long been used as such. It now seems that many of these agents might have therapeutic value in several common neurodegenerative conditions, independently of their inhibition of monoamine oxidase activity. However, many claims and some counter-claims have been made about the physiological importance of these enzymes and the potential of their inhibitors. We evaluate these arguments in the light of what we know, and still have to learn, of the structure, function and genetics of the monoamine oxidases and the disparate actions of their inhibitors.

The therapeutic potential of monoamine oxidase inhibitors.

Do Novel Antipsychotics Have Similar Pharmacological Characteristics? A Review of the Evidence

Specific in vitro and in vivo binding of 3H-raclopride a potent substituted benzamide drug with high affinity for dopamine D-2 receptors in the rat brain

https://www.cell.com/trends/neurosciences/pdf/S0166-2236(00)01996-2.pdf

Molecular basis of aggression

Background: Quetiapine is a new atypical antipsychotic medication. As such, relatively little has been published regarding its in vivo effects at the dopamine type 2( D 2) and serotonin type 2a (5-HT2a) receptor systems. The following study was undertaken to explore these effects across the clinical dose range and relate this information to its clinical profile. Methods: Twelve patients with schizophrenia were randomly assigned to doses of 150 to 600 mg/d (n=3, at 150, 300, 450, and 600 mg/d) of quetiapine. After 3 weeks of treatment, D2 and 5-HT2a occupancy were measured using positron emission tomography (PET) imaging, 12 to 14 hours after the last dose. Clinical efficacy and adverse effect ratings were obtained at baseline, at the time of PET scanning, and at 12 weeks. Two additional patients were included to examine the effects of the drug 2 to 3 hours after last dose. Results: Quetiapine was an effective antipsychotic and improved the extrapyramidal symptoms and prolactin level elevation noted at baseline. It achieved these results with minimal (0%-27%) D2 occupancy 12 hours after the last dose. Study of the additional subjects revealed that quetiapine does give rise to transiently high (58%-64%) D2 occupancy 2 to 3 hours after a single dose that then decreases to minimal levels in 12 hours. Conclusions: Quetiapine shows a transiently high D2 occupancy, which decreases to very low levels by the end of the dosing interval. Quetiapine’s low D2 occupancy can explain its freedom from extrapyramidal symptoms and prolactin level elevation. The data suggest that transient D2 occupancy may be sufficient for its antipsychotic effect. Future studies controlling for nonpharmacological effects as well as activities on other receptors will be necessary to confirm this suggestion.

A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy.

Remoxipride, a new potential antipsychotic compound with selective anti-dopaminergic actions in the rat brain

A series of some novel N-(l-ethyl-2-pyrrolidinylmethyl)benzamides was synthesized and tested for dopamine receptor blockade in vivo by the ability to block the apomorphine syndrome in the rat. Several compounds were considerably more potent than sulpiride as dopamine receptor blockers and displayed low liability to induce extrapyramidal side effects (catalepsy) in the rat. The blockade of dopamine receptor activity in vivo was mainly confined to the levorotatory isomers having the S absolute configuration. The structure-activity relationships are discussed.

Potential neuroleptic agents. 2,6-Dialkoxybenzamide derivatives with potent dopamine receptor blocking activities.

A series of substituted 6-methoxysalicylamides were synthesized from their corresponding 2,6-dimethoxybenzamides by demethylation of one methoxy group with boron tribromide. Substituted 6-methoxysalicylamides having a lipophilic aromatic substituent in the 3-position para with respect to the methoxy group, e.g. a bromo or an iodo atom or an ethyl or a propyl group, and having an (S)-N-(1-alkyl-2-pyrrolidinyl)methyl moiety as the side chain were found to be potent blockers of [3H]spiperone binding in vitro and potent inhibitors of the apomorphine syndrome in the rat. Similar to remoxipride but in contrast to haloperidol, some of the substituted salicylamides show a 10-20-fold separation between the dose that inhibits hyperactivity and that which inhibits stereotypy. It was concluded that, besides the requirement of a lipophilic substituent in the position para to the methoxy group for antidopamine activity in vivo, the formation of a coplanar six-membered pseudoring involving the amide moiety and the methoxy group is a structural requirement for activity in vitro.

Potential neuroleptic agents. 3. Chemistry and antidopaminergic properties of substituted 6-methoxysalicylamides.

A series of derivatives of 4-aminophenethylamine was synthesized and their effect on monoamine oxidase (MAO) activity in the brain was evaluated. Several of the new compounds were potent and selective inhibitors of the A form of MAO but were poor inhibitors of the B form. The most active compounds were the 2,6-dichloro-(9) and the 2-halogeno-4-dimethylaminophenethylamines (5, 6, and 8). Some of the compounds also strongly antagonized aggressive behavior in isolated male mice. This effect was correlated to the MAO inhibition when tyramine was used as substrate. Significant correlations between MAO inhibition in vivo and potentiation of the syndromes produced by 5-hydroxytryptophan and tryptamine and antagonism of reserpine sedation were obtained.

Selective monoamine oxidase inhibitors. 1. Compounds related to 4-aminophenethylamine.

Nine 4-aminophenethylamine derivatives were synthesized and tested for monoamine oxidase (MAO) inhibitory effects with particular attention to their selectivity for MAO within monoaminergic neurons in the rat brain. All compounds selectively inhibited the A form of MAO in vitro. Some of the compounds inhibited the MAO within the monoaminergic neurons at much lower doses than those required for inhibition of MAO within other cells in vivo. The most potent compounds in this respect were 4-amino-2-fluoro-alpha-methylphenethylamine (5) and 4-amino-2-chloro-alpha-methylphenethylamine (4).

Lennart Florvall

Papers

Remoxipride, a new potential antipsychotic compound with selective anti-dopaminergic actions in the rat brain

Potential neuroleptic agents. 2,6-Dialkoxybenzamide derivatives with potent dopamine receptor blocking activities.

Potential neuroleptic agents. 3. Chemistry and antidopaminergic properties of substituted 6-methoxysalicylamides.

Selective monoamine oxidase inhibitors. 1. Compounds related to 4-aminophenethylamine.

Selective monoamine oxidase inhibitors. 4. 4-Aminophenethylamine derivatives with neuron-selective action.