John P. M. Finberg

Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug

The present study of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane(Z) hydrochloride, was undertaken to determine its biochemical profile. The properties of midalcipran, in inhibiting the uptake of monoamines were tested and compared with that of imipramine. In vitro, midalcipran was found to inhibit the uptake of radiolabelled serotonin and noradrenaline (IC50 = 203 and 100 nM, respectively), but not that of dopamine, into brain slices. Hyperthermia induced by the centrally-acting displacers of monoamines, H77/77 and H75/12, were almost equipotently antagonized by midalcipran, confirming the inhibition of the uptake of serotonin and noradrenaline by midalcipran in vivo (ID50 = 11 and 4.8 mg/kg, respectively). Midalcipran showed no inhibition of the activity of monoamine oxidase in vitro or in vivo. The interaction between midalcipran and neurotransmitter receptors and binding sites in the CNS was studied in the rat in comparison with imipramine and desipramine. In contrast to these two antidepressant drugs, midalcipran showed no affinity for alpha- or beta-adrenoceptors, muscarinic, histaminergic H1, dopaminergic D2 or serotonergic 5-HT2 receptors, suggesting a general absence of anticholinergic, sedative and other side-effects. Midalcipran was equipotent with imipramine at inhibiting the binding of [3H]imipramine. Chronic administration of midalcipran to rats did not alter the number of beta-adrenergic receptors in the cortex, in contrast to imipramine and desipramine which decreased the binding of beta-adrenoceptors. Thus midalcipran appears to act exclusively presynaptically, inhibiting the uptake of serotonin and noradrenaline. This activity, coupled to the total absence of interaction at postsynaptic sites, suggests that midalcipran may be a useful and novel antidepressant drug.

New directions in monoamine oxidase A and B selective inhibitors and substrates

Identification, cellular localization, and cDNA cloning of MAO subtypes A and B have increased the insight into the pharmacology of these enzymes, whose primary functions are intra- and extraneuronal inactivation of neurotransmitter (dopamine, noradrenaline and serotonin) and other biogenic amines. In addition, MAO oxidizes the inert uncharacteristic tertiary amine, MPTP, to the parkinson inducing dopaminergic neurotoxin, MPP+, and the novel secondary amine anticonvulsant milacemide to the inhibitory amino acid neurotransmitter, glycine. These recent developments have provided new therapeutic perspectives for the management of Parkinsons disease and seizure disorders via the use of selective inhibitors and amino acid amine prodrug substrates of MAO-B.

Update on the pharmacology of selective inhibitors of MAO-A and MAO-B: Focus on modulation of CNS monoamine neurotransmitter release

Inhibitors of monoamine oxidase (MAO) were initially used in medicine following the discovery of their antidepressant action. Subsequently their ability to potentiate the effects of an indirectly-acting sympathomimetic amine such as tyramine was discovered, leading to their limitation in clinical use, except for cases of treatment-resistant depression. More recently, the understanding that: a) potentiation of indirectly-acting sympathomimetic amines is caused by inhibitors of MAO-A but not by inhibitors of MAO-B, and b) that reversible inhibitors of MAO-A cause minimal tyramine potentiation, has led to their re-introduction to clinical use for treatment of depression (reversible MAO-A inhibitors and new dose form MAO-B inhibitor) and treatment of Parkinsons disease (MAO-B inhibitors). The profound neuroprotective properties of propargyl-based inhibitors of MAO-B in preclinical experiments have drawn attention to the possibility of employing these drugs for their neuroprotective effect in neurodegenerative diseases, and have raised the question of the involvement of the MAO-mediated reaction as a source of reactive free radicals. Despite the long-standing history of MAO inhibitors in medicine, the way in which they affect neuronal release of monoamine neurotransmitters is still poorly understood. In recent years, the detailed chemical structure of MAO-B and MAO-A has become available, providing new possibilities for synthesis of mechanism-based inhibitors. This review describes the latest advances in understanding the way in which MAO inhibitors affect the release of the monoamine neurotransmitters dopamine, noradrenaline and serotonin (5-HT) in the CNS, with an accent on the importance of these effects for the clinical actions of the drugs.

Increased striatal dopamine production from L-DOPA following selective inhibition of monoamine oxidase B by R(+)-N-propargyl-1-aminoindan (rasagiline) in the monkey

Striatal extracellular fluid concentrations of dopamine and metabolites in response to direct striatal administration of two L-DOPA boluses administered sequentially were determined in three rhesus monkeys during halothane anesthesia. Whereas in an initial microdialysis run, generation of dopamine was less following the second L-DOPA bolus than the first, in a subsequent run, in which the selective MAO-B inhibitor R(+)-N-propargyl-1-aminoindan (rasagiline) was administered systemically (0.2 mg/kg s.c.) between the two L-DOPA boluses, generation of dopamine was greater following the second bolus.

Copper pathology in vulnerable brain regions in Parkinson's disease.

Synchrotron-based x-ray fluorescence microscopy, immunofluorescence, and Western blotting were used to investigate changes in copper (Cu) and Cu-associated pathways in the vulnerable substantia nigra (SN) and locus coeruleus (LC) and in nondegenerating brain regions in cases of Parkinsons disease (PD) and appropriate healthy and disease controls. In PD and incidental Lewy body disease, levels of Cu and Cu transporter protein 1, were significantly reduced in surviving neurons in the SN and LC. Specific activity of the cuproprotein superoxide dismutase 1 was unchanged in the SN in PD but was enhanced in the parkinsonian anterior cingulate cortex, a region with α-synuclein pathology, normal Cu, and limited cell loss. These data suggest that regions affected by α-synuclein pathology may display enhanced vulnerability and cell loss if Cu-dependent protective mechanisms are compromised. Additional investigation of copper pathology in PD may identify novel targets for the development of protective therapies for this disorder.

Effect of Iron Chelators on Dopamine D2 Receptors

Abstract: Nutritional iron deficiency induced in rats causes a selective reduction of [3H]spiperone binding in caudate nucleus. This effect can be reversed by iron supplementation in vivo. The possibility that iron may be involved in the dopamine D2 receptor was investigated by examining the effect of various iron and noniron chelators on the binding of [3H]spiperone in rat caudate nucleus. Iron chelators 1, 10‐phenanthroline, 2,4,6‐tripyridyl‐s‐triazine, α,α′‐dipyridyl, and desferrioxamine mesylate inhibited the binding of [3H]spiperone. The inhibition by 1,10‐phenanthroline was noncompetitive and reversible. In the presence of FeCl2 or FeCl3, the inhibitory effect of 1,10‐phenanthroline was potentiated. Iron salts or chelators were without effect on the binding of [3H]dihydroalprenolol to β‐adrenoreceptors in caudate nucleus; thus the action of iron chelators on the dopamine D2 receptor tends to be selective. Incubation of caudate nucleus membrane prepared from iron‐deficient rats with FeCl2 or FeCl3 did not reverse the diminished binding of [3H]spiperone. The present study indicates that if iron is involved in the physiological regulation of dopamine D2 agonist‐antagonist binding sites, it is more complex than hitherto considered.

Prevention of MPTP-induced neurotoxicity by AGN-1133 and AGN-1135, selective inhibitors of monoamine oxidase-B

Two selective and potent inhibitors of monoamine oxidase (MAO) type B, namely AGN-1133 (N-methyl-N-propynyl-1-indanamine) and AGN-1135 (N-propynyl-1-indanamine), given to mice prior to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) protected against the neurotoxic effects of MPTP. For example, mice treated with these agents prior to MPTP, did not exhibit the decrement in the neostriatal content of dopamine and its metabolites normally seen after MPTP administration. These data lend further support to the concept that the oxidation of MPTP by MAO-B to its corresponding pyridinium analog, 1-methyl-4-phenyl-pyridinium (MPP+) is an important feature of the neurotoxic process.

Pharmacological properties of the anti-Parkinson drug rasagiline; modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviours.

Rasagiline [N-propargyl-1R(+)-aminoindan; TVP1012] is a potent irreversible monoamine oxidase (MAO) inhibitor with selectivity for type B of the enzyme, which is being developed for treatment of Parkinsons disease. In this study we examined effects of rasagiline on CNS monoamine levels, modification of behavioural response to L-tryptophan, fluoxetine and L-DOPA, and reversal of reserpine syndrome. Reserpine-induced ptosis was reversed by rasagiline at doses above 2 mg x kg(-1) i.p., which inhibit MAO-A as well as MAO-B, but not at MAO-B-selective doses. However, combination of rasagiline (10 mg x kg(-1) i.p.) with L-DOPA or L-tryptophan (50 mg x kg(-1) i.p.), or rasagiline (10 mg x kg(-1) p.o.) with fluoxetine (10 mg x kg(-1) p.o.), did not induce the behavioural hyperactivity syndrome which is seen following inhibition of both MAO-A and MAO-B by tranylcypromine together with the monoamine precursors. Following oral administration, levels of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and dopamine (DA) were unaffected in hippocampus and striatum after single doses of rasagiline up to 2 mg x kg(-1). Following chronic oral administration (21 days, one dose daily), levels of NA, 5-HT and DA in hippocampus and striatum were unaffected by rasagiline at doses up to 1 mg x kg(-1). Rasagiline does not modify CNS monoamine tissue levels or monoamine-induced behavioural syndromes at doses which selectively inhibit MAO-B but not MAO-A.

Jaundice, the Circulation and the Kidney

(Fig. 1) Cholemia per se (i.e. independent of parenchymal liver damage) causes a profound disturbance of systemic hemodynamics. This includes decrease in total peripheral vascular resistance, and possible impairment of left ventricular performance. These, in turn, lead to a decrease in effective blood volume, a tendency to hemorrhagic shock and prerenal failure. Early in the course of cholemia , the natriuretic effects of bile salts in the circulation may aggravate the hypovolemia. In marked contrast to the decrease in total peripheral vascular resistance, the regional vascular beds of the kidney and the brain constrict during cholemia . The combined effect of cholemia may thus lead to redistribution of cardiac output away from the kidney and the brain. When parenchymal liver damage complicates obstructive jaundice, the tendency to arterial hypotension is aggravated. The overall interrelationship between jaundice and circulatory homeostasis is depicted in figure 1.

Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology.

Inhibitors of MAO-A and MAO-B are in clinical use for the treatment of psychiatric and neurological disorders respectively. Elucidation of the molecular structure of the active sites of the enzymes has enabled a precise determination of the way in which substrates and inhibitor molecules are metabolized, or inhibit metabolism of substrates, respectively. Despite the knowledge of the strong antidepressant efficacy of irreversible MAO inhibitors, their clinical use has been limited by their side effect of potentiation of the cardiovascular effects of dietary amines (“cheese effect”). A number of reversible MAO-A inhibitors which are devoid of cheese effect have been described in the literature, but only one, moclobemide, is currently in clinical use. The irreversible inhibitors of MAO-B, selegiline and rasagiline, are used clinically in treatment of Parkinsons disease, and a recently introduced reversible MAO-B inhibitor, safinamide, has also been found efficacious. Modification of the pharmacokinetic characteristics of selegiline by transdermal administration has led to the development of a new drug form for treatment of depression. The clinical potential of MAO inhibitors together with detailed knowledge of the enzymes binding site structure should lead to future developments with these drugs.