(R)-N-(2-Heptyl)-N-methyl-propargylamine (R-2HMP) and (R)-N-(2-heptyl)-propargylamine (R-2HPA) are analogs of R-deprenyl. R-Deprenyl, a selective monoamine oxidase B inhibitor, is a mechanism-based inactivator of purified CYP2B1. The aim of the present study was to determine whether R-2HMP and R-2HPA behaved like deprenyl with respect to inhibiting cytochrome P450 (CYP450) enzyme activity. The activities of CYP1A2 and CYP1A1 were assessed by measuring the deethylation of 7-ethoxyresorufin by liver microsomes obtained from control and beta-naphthoflavone-treated female Wistar rats, respectively. CYP2B1 activity was assessed by measuring depentylation of 7-pentoxyresorufin by liver microsomes obtained from phenobarbital-treated rats. The activity of CYP1A1 was unaffected by 100 microM concentrations of R-deprenyl, R-2HMP, or R-2HPA. In contrast, the activities of CYP1A2 and CYP2B1 were significantly decreased. In general, the percentage of CYP1A2 activity remaining in the presence of 100 microM of one of these propargylamines ranged from 45 to 56%, whereas 10% or less of CYP2B1 activity remained. No marked differences between the various propargylamines were observed. The IC(50) values for the inhibition of CYP2B1 activity by R-deprenyl, R-2HMP, and R-2HPA were found to be 2.6, 8.5, and 3.6 microM, respectively. The S-enantiomers of deprenyl, 2HMP, and 2HPA also inhibited the activity of microsomal CYP2B1. R-2HMP, R-2HPA, and S-2HPA were found to be mechanism-based inactivators of CYP2B1 activity. The inactivation constants k(inact) and K(I) were found to be as follows: R-deprenyl, 1.3 microM and 0.32 min(-1); R-2HMP, 0.8 microM and 0.08 min(-1); R-2HPA, 0.5 microM and 0.36 min(-1); and S-2HPA, 0.24 microM and 0.18 min(-1).

(R)-N-(2-Heptyl)-N-methylpropargylamine (R-2HMP) is a monoamine oxidase inhibitor and putative antiapoptotic agent analogous to (R)-deprenyl. In the rat, the major amine metabolites of R-2HMP have been identified as (R)-N-2-heptylmethylamine (R-2HMA), (R)-N-2-heptylpropargylamine (R-2HPA), and (R)-2-heptylamine (R-2HA). After R-2HMP was administered s.c. to male Wistar rats, it was observed that the greatest concentration was of the original drug followed in decreasing order by R-2HMA, R-2HPA, and R-2HA in brain, liver, and plasma at all times after administration. The greatest concentrations of the three metabolites were found in brain followed by liver and plasma, and the peak concentrations occurred between 15 and 30 min after administration. After oral administration, the liver contained the greatest concentrations of drug and metabolites, and, again, the peak concentrations occurred at about 15 min. In all cases, depropargylation appears to occur at a faster rate than demethylation. After s.c. administration, R-2HMP and its metabolites exhibited biexponential redistribution and elimination losses. Half-lives of the compounds in brain for the redistribution phase were: R-2HMP, 10 min; R-2HMA, 11 min; R-2HPA, 16 min; and R-2HA, 15 min.

A number of N-substituted-propargylamines are well known mechanism-based MAO inhibitors. Clorgyline and deprenyl in fact represent archetypal MAO-A and MAO-B inhibitors respectively. In the present study several ring-substituted deprenyl structural analogues were synthesized and alterations of selectivity and potency towards MAO-A and MAO-B activities were found. When deprenyl and its structural analogues were further modified to their corresponding quaternary ammonium salts, i.e. by attaching either an extra propargyl or a methyl group to the nitrogen atom, the potency of inhibition of MAO-B activity was drastically reduced and inhibition of MAO-A activity substantially increased. Such a complete inversion of selectivity may be related to a hydrophilic and electrophilic region seemingly present only in the MAO-A but not in the MAO-B molecule. The results also suggest that at least three sites are required for the selectivity and mechanism-based action of an inhibitor towards MAO.

Deprenyl is the archetypical monoamine oxidase (MAO)-B inhibitor. It has been shown to offer symptomatic relief in the treatment of Parkinson's patients, and it has also been claimed to be neuroprotective. Possible disadvantages are its amphetaminergic metabolites and dopamine uptake-blocking properties. In addition, because its neurorescue effects were discovered somewhat serendipitously, it is quite possible that other MAO-B inhibitors or even different classes of compounds could be better rescue agents. Structure activity studies in which changes in the nature of the groups attached to the nitrogen atom, including the effects of chain length substitutions at either the α-carbon atom or on the terminal carbon atom or unsaturation or remote branching revealed that MAO activity is eliminated if the methyl group on the nitrogen atom is changed, optimum potency and selectivity are achieved by the blocking group being either propargyl or 2-butyn-1-yl, four to seven carbon branched-chain compounds are as potent as, or more potent than, deprenyl as MAO inhibitors in vivo. In vitro, they are somewhat less effective than deprenyl. In vivo and in vitro selectivity of the1- and 2-hexyl analogues is much superior to deprenyl. The presence of unsaturation or branching (at other than α carbon) has no effect on potency or selectivity; the presence of both, however, in some cases produced a marked increase in selectivity. Substituting with hydroxyl or carbethoxy groups destroys MAO inhibiting activity. This chapter summarizes that studies have demonstrated new mechanisms of action for most MAO-B inhibitors, which raise the intriguing question of what is MAO-B really doing? The inhibitors are antiapoptotic at very low concentrations, although their site of action in the apoptotic cascade is not yet clear. The possibility that some of these MAO-B inhibitor drugs will find a use in the treatment of various neurodegenerative disorders and stroke seems quite promising.

Several clinical investigations have indicated that R-deprenyl, a typical monoamine oxidas B inhibitor, delays the progression of Parkinson's and Alzheimer's disease. A number of aliphatic N-methylpropargylamines, such as R-2-hexyl-N-methylpropargylamines (R-2HxMP), have been found to be highly potent, irreversible, selective, MAO-B inhibitors both in vitro and in vivo. These aliphatic propargylamines do not affect noradrenaline of dopamine uptake and are chemically without an amphetamine moiety and therefore do not exhibit any amphetamine-like effects. They are capable of protecting mouse striatal dopamine neurons against MPTP-induced toxicity in the caudate, against MK-801-induced apoptosis in the retrosplenial cortex and against DSP-4-induced depletion of naradrenergic axons. They rescue hippocampal neurons in rodents following kainate-induced neuronal damage. They block the expression of heat shock protein (HSP70) and delayed c-Fos expression in hippocampal CA1 region as elicited by kainate. Confocal microscopy also revealed prevention of neuronal damage in hippocampal slices under hypoxia-hypoglycemia conditions. Aliphatic N-methylpropargylamines may be useful in the treatment of neurodegenerative disorders. The mechanism and site of action of the neurorescue effect of these propargylamines, however, remains to be established.

The chromatographic properties of (R)-(+)-N-(trifluoroacetyl)prolyl and (S)-(-)-N-(trifluoroacetyl)prolyl derivatives on a chiral gas chromatography capillary column were assessed for the measurement of enantiomeric purities of 2-butylamine, 2-pentylamine, 2-hexylamine, 2-heptylamine and 2-octylamine and their N-methyl analogues, which are used as precursors in the synthesis of some selective, specific, irreversible monoamine oxidase-B inhibitors. Using a Chirasil-Val column it was possible to separate all four diastereomers of the primary amines, and three of the four isomers of the secondary amines. Quantitation of the enantiomers is facilitated even with enantiomerically impure reagent when compared to the use of an achiral phase.

Two series of drugs, the aliphatic-N-methyl propargylamines and the aliphatic propargylamines, have been synthesised and shown to be specific, irreversible, and potent monoamine oxidase B inhibitors and neural rescue agents. In the latter case, an absolute stereochemical requirement for the R isomer exists. Both series of compounds have been shown, in numerous in vitro and in vivo experimental paradigms, to be effective neuronal rescue agents. Candidates from both series exhibit excellent bioavailability and pharmacokinetics and offer opportunities for treating neurodegenerative disorders and stroke and cognitive decline in companion animals. (C) 1997 Wiley-Liss, Inc.

DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] is a potent neurotoxin highly selective to the locus coeruleus noradrenaline (NA) system. Previous biochemical studies have shown that the monoamine oxidase-B (MAO-B) inhibitors, R(-)-deprenyl and (+/-)2-HxMP [N-(2-hexyl)-N-methylpropargylamine], are able to prevent DSP-4 induced NA depletion in the mouse hippocampus. It is not quite certain, however, whether this actually represents neuroprotection of NA axons or a metabolic effect due to inhibition of MAO activity. Employing dopamine-beta-hydroxylase immunohistochemical and image analysis methods, we have shown that 92% and 84% of NA nerve fibers in the rat hippocampus are spared from DSP-4 neurotoxicity by a single pretreatment dose of either R(-)-deprenyl or (+/-)2-HxMP respectively. Similar neuroprotective effects of R(-)-deprenyl and (+/-)2-HxMP were also observed in the cerebral cortex, thalamus, amygdaloid complex and cerebellum. This is the first morphological evidence demonstrating that R(-)-deprenyl and (+/-)2-HxMP can indeed protect noradrenergic axons of locus coeruleus origin against DSP-4 neurotoxicity.

A series of aliphatic N-methylpropargylamine MAO-B inhibitors have been synthesized and their structural and functional relationships have been investigated. 2-Hexyl-N-methylpropargylamine (2-HxMP), for example, has been found to be a highly potent, irreversible, selective, MAO-B inhibitor both in vitro and in vivo. The R-(-)-enantiomers are much more active than the S-(+)-enantiomers at inhibiting MAO-B activity. Some of these compounds protect mouse nigrostriatal dopamine neurons against the neurotoxin MPTP and the mouse hippocampal noradrenergic system against the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). They rescue hippocampal neurons after damage induced by ischemia and kainic acid treatment, as well as motoneurons in young mice following facial nerve axotomy. Such rescue effects are, interestingly, unrelated to inhibition of MAO-B activity. Some of the aliphatic propargylamines enhance the survival of neuroblastoma cells co-cultured with astrocytes following serum depletion. They stimulate the expression of AADC mRNA and inhibit GFAP mRNA expression. They do not possess amphetamine-like properties and exhibit no effect on noradrenaline or dopamine uptake nor do they increase hypertensive effects in the tyramine pressor test. Unlike R(-)-deprenyl, 2-HxMP does not potentiate dopamine toxicity in vitro. These new MAO-B inhibitors may possess significant chemotherapeutic implications for certain psychiatric and neurodegenerative disorders.

Dogs were administered capsules containing L-deprenyl daily over 3 weeks at dose levels of 0, 0.1, 0.5, and 1.0 mg/kg. Spontaneous behavior was measured using a canine open field test, and was not significantly affected by L-deprenyl. Plasma levels of amphetamine showed a clear dose-dependent elevation 2 h and was not significantly affected by L-deprenyl. Plasma levels of amphetamine showed a clear dose-dependent elevation 2 h following treatment, but were markedly lower after 24 h, and were undetectable 5 days following the last treatment. Plasma levels of phenylethylamine were increased, but were highly variable. Animals sacrificed 1 day following the last treatment showed a dose-dependent inhibition of monoamine oxidase B in the brain, liver, and kidney, whereas monoamine oxidase A was unaffected in these tissues. L-Deprenyl also caused an increase in phenylethylamine in the striatum and hypothalamus, but not in the neocortex. Brain levels of DA, DOPAC, 3-MT, HVA, 5-HT, and 5-HIAA were unaffected. The pharmacological profile for the dog is distinct from that of other species in that long-term treatment did not produce any significant inhibition of MAO-A activity. The absence of an effect on biogenic amines or metabolites suggests that the metabolism of dopamine is mediated at least in part through pathways other than MAO-B in the normal adult dog.

1-Deprenyl, a selective irreversible MAO-B inhibitor, has been shown to prolong the onset of disability in Parkinson's patients and to improve cognitive behavior in Alzheimer's disease. It has been claimed that 1-deprenyl exhibits neuroprotective and neurorescue effects in several animal models. The precise mechanism of these effects is unknown. It is yet to be established whether or not the effects are unique to 1-deprenyl; a drug which possesses, in addition to inhibition of MAO-B activity, an amphetamine moiety. Based on the fact that several N-methylpropargylamine derivatives have been shown to be MAO inhibitors and that aliphatic amines are typical MAO-B substrates with a high affinity for the enzyme, we have synthesized a series of aliphatic propargylamines which have turned out to be highly potent, selective and irreversible MAO-B inhibitors, structurally unrelated to amphetamine. The potency of these inhibitors is related to their chain length and the substitution of a hydrogen on the terminal carbon of the aliphatic chain. MAO-I activity, as assessed in vitro, increased as the aliphatic carbon chain length increased; substitution of the hydrogen at the aliphatic chain terminal by hydroxyl, carboxyl or carboethoxyl groups or replacement of the methyl group on the nitrogen atom by an ethyl group considerably reduced their inhibitory activity. Stereospecific effects were observed with the R-(-)-enantiomer being 20-fold more active than the S-(+)-enantiomer. Inhibitors with relatively short carbon chain lengths (i.e. four to six carbons) were found to be more potent at inhibiting brain MAO-B activity in vivo especially after oral administration.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study has examined whether MAO-B has a role in DA metabolism in the primate CNS in situ. Eleven macaques (macaca facicularis) were used in this study to examine the effects of (-)-deprenyl (1 mg/kg, i.v., 2 and 24 hours). (-)-Deprenyl administration completely and selectively blocked MAO-B activity and blocked DA metabolism in the caudate nucleus and frontal cortex. DA metabolism in the substantia nigra was not affected by MAO-B inhibition. Changes in DA metabolism were accompanied by changes in 5-hydroxytryptamine (5HT) turnover: 5-hydroxyindole acetic acid (5HIAA) levels increased in the caudate and decreased in the frontal cortex. Levels of 2-phenylethylamine (PE), a putative modulator of dopaminergic transmission, were increased by MAO-B inhibition in all three brain regions examined. It is concluded that in some regions of the primate brain, in contrast to the rat, MAO-B has an important role in DA metabolism.

Semicarbazide-sensitive amine oxidases (SSAOs) are located in cardiovascular smooth muscle, cartilage and brown adipose tissues of different species, including human. The enzyme is also present in blood, and its activity appears to be altered under certain pathological conditions. SSAOs from both human umbilical arteries and serum were partially purified, and some of their biochemical properties were investigated. Both human artery and blood SSAO exhibited very similar substrate preference, lack of stereospecificity catalyzing the deamination of pro-R and pro-S benzylamine-deuterated enantiomers, and were very sensitive towards (E)-2-(4-fluorophenethyl)-3-fluoroallylamine (MDL-72974A). It was concluded that circulating serum SSAO is identical to the SSAO from vascular tissues. Human SSAO exhibited distinctly different properties in comparison to bovine and rat SSAOs.

Semicarbazide-sensitive amine oxidases (SSAOs) are located in cardiovascular smooth muscle, cartilage and brown adipose tissues of different species, including human. The enzyme is also present in blood, and its activity appears to be altered under certain pathological conditions. SSAOs from both human umbilical arteries and serum were partially purified, and some of their biochemical properties were investigated. Both human artery and blood SSAO exhibited very similar substrate preference, lack of stereospecificity catalyzing the deamination of pro-R and pro-S benzylamine-deuterated enantiomers, and were very sensitive towards (E)-2-(4-fluorophenethyl)-3-fluoroallylamine (MDL-72974A). It was concluded that circulating serum SSAO is identical to the SSAO from vascular tissues. Human SSAO exhibited distinctly different properties in comparison to bovine and rat SSAOs.

O'Reilly, Richard L. and Bruce A. Davis: Phenylethylamine and Schizophrenia. Frog. Neuro-Psychopharmacol. and Biol. Psychiat. 1994, 18(1): 63-75. 1. The evidence that phenylethylamine (PEA) plays a role in the etiology of schizophrenia is reviewed. 2. PEA shares structural and physiological similarities with the amphetamines, the administration of which can induce a schizophrenia-like psychosis. 3. While there are a number of reports of high urinary PEA excretion in schizophrenic patients, the measurement of PEA in other body fluids and the measurement of phenylacetic acid (the major metabolite of PEA) has resulted in inconsistent findings. 4. The use of neuroleptic medication is a major confounding variable in most of the clinical studies. If PEA does have a role in the etiology of schizophrenia, the mechanism may involve PEAs ability to amplify dopamine responses.

Women with bulimia nervosa undergoing treatment with the reversible monoamine oxidase type A inhibitor, brofaromine, were rated for mood and eating behaviour and their plasma and urine were assessed for phenylacetic acid (unconjugated and total) and unconjugated phenylethylamine prior to and after four weeks of drug treatment. Changes in plasma unconjugated phenylacetic acid concentrations were significantly and negatively correlated with the corresponding changes in Hamilton Depression scores but not with eating behavior measures. There were no significant correlations between changes in phenylethylamine levels and changes in rating scores. Patients diagnosed as suffering concurrently from severe depression (Hamilton Depression score of 17 or higher) had lower plasma and urinary phenylacetic acid levels than did those whose depression was not severe (Hamilton score less than 17). Phenylethylamine concentrations were not different between the severely and mildly depressed subgroups. The results confirm earlier studies on the relationship between phenylacetic acid and depression while showing that a similar relationship does not pertain to phenylacetic acid and eating behavior in bulimia nervosa.

Abstract: DSP‐4 [N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine], a selective noradrenaline (NA) uptake blocker, is capable of inducing long‐lasting depletion of NA in some noradrenergic axon terminals and of subsequently causing cell death to NA neuronal cell bodies in rodents. R(−)‐Deprenyl, a selective monoamine oxidase (MAO)‐B inhibitor, has been shown to be capable of protecting animals against this DSP‐4‐induced neuronal degeneration. Its action, however, has been claimed to be unrelated to the inhibition of MAO‐B activity but rather due to competition for the NA uptake sites. The effects of several types of MAO inhibitors against DSP‐4 toxicity, MAO‐B activity both in vivo and in vitro, and NA uptake into the hippocampus have been assessed. N‐(2‐Hexyl)‐N‐methylpropargylamine (2‐HxMP), a potent MAO‐B inhibitor, for example, exerts no appreciable effect on NA uptake but is quite potent in counteracting the NA‐depleting effect of DSP‐4. Such results rule out the possibility that the neuroprotective effect of the MAO‐B inhibitors is due mainly to their effect on NA uptake. The in vitro inhibition of MAO‐B activity seems to correlate positively with their neuroprotective effects against DSP‐4. In comparison to the MAO‐B inhibitors, NA uptake blockers, such as desipramine and S(+)‐deprenyl, exhibit relatively low efficacy in protecting the NA axon terminals from the effects of DSP‐4‐induced damage. The restoration of hippocampal NA levels is significantly enhanced with repeated treatments of R(−)‐deprenyl or 2‐HxMP even at very low doses following the DSP‐4 insult. This suggests that in addition to neuroprotection, these MAO‐B inhibitors may rescue some of the noradrenergic axon terminals damaged by DSP‐4.

Straight and branched chain aliphatic monoamines, which are not normal tissue constituents, are deaminated selectively by type B monoamine oxidase (MAO-B). They exhibit a high affinity towards the active site of MAO-B and this made them very useful pharmacologically. An anticonvulsant prodrug, Milacemide [2-(N-pentyl)glycinamide] is deaminated by MAO-B and this facilitates a mechanism of delivering glycine into the CNS. We have found that 2-propyl-pentylamine (2-propyl-1-aminopentane) and N-(2-propylpentyl)glycinamide are also converted by MAO-B to valproic acid and glycine both in vitro and in vivo; these compounds, however, cause severe tremor. By attaching a propargylamine group the resultant series of aliphatic propargylamine derivatives have been shown to be very potent selective MAO-B inhibitors. They are chemically quite different from most other MAO-B inhibitors, since they do not possess any aromatic structures. The relatively short chain aliphatic propargylamines, i.e. N-2-pentyl-N-methylpropargylamine and N-2-hexyl-N-methylpropargylamine, are 4 to 5 times more potent and more selective than selegiline (1-deprenyl) with respect to the inhibition of MAO-B in brain following oral administration. Semicarbazide-sensitive amine oxidase (SSAO) catalyzes the deamination of not only longer chain aliphatic amines but also short chain aliphatic amines including methylamine. Formaldehyde is produced from methylamine by SSAO. Increased methylamine deamination may cause cellular damage in some pathological conditions, such as uraemia and diabetes. We have observed that cultured human endothelial cells are damaged by methylamine in the presence of SSAO. Inhibition of the SSAO activity completely protects these cells from the methylamine-SSAO induced damage.

Abstract: Aliphatic N‐propargylamines have recently been discovered to be highly potent, selective, and irreversible monoamine oxidase B (MAO‐B) inhibitors. N‐Methyl‐N‐(2‐pentyl)propargylamine (M‐2‐PP) and N‐methyl‐N‐(2‐hexyl) propargylamine (2‐HxMP), for example, are approximately fivefold more potent than I‐deprenyl at inhibiting mouse brain MAO‐B activity following oral administration. These inhibitors are nonaromatic compounds and are chemically quite different from other known MAO‐B inhibitors. Some of their neurochemical and neuroprotective properties have been evaluated and compared with those of I‐deprenyl. We have confirmed that these new inhibitors selectively inhibit MAO‐B activity both in vitro and in vivo. 2‐Phenylethylamine levels were substantially increased following administration of M‐2‐PP, but the levels of dopamine, 3,4‐dihydroxyphenylacetic acid, homovanillic acid, 5‐hydroxytryptamine, and 5‐hydroxyindoleacetic acid were not affected except at high, nonselective doses. Chronic oral administration of I‐deprenyl and M‐2‐PP causes selective inhibition of MAO‐B activity and increases dopamine levels in mouse caudate. M‐2‐PP, like I‐deprenyl, has been shown to be potent in protecting against MPTP‐induced damage in the mouse. N‐(2‐Chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP‐4), a noradrenaline neurotoxin, is not an MAO substrate. Its noradrenaline‐depleting effects were substantially mitigated by I‐deprenyl as well as by M‐2‐PP and 2‐HxMP in the mouse hippocampus. Administration of 2‐phenylethylamine, however, failed to reverse the effect of DSP‐4. The neuroprotective effect of M‐2‐PP and 2‐HxMP is apparently unrelated to the uptake of DSP‐4.