Rasagiline

Rasagiline is a second-generation potent, irreversible and selective inhibitor of monoamine-oxidase type B (MAO-B), which has been evaluated for the treatment of Parkinson's disease. Rasagiline also possesses neuroprotective properties that are independent of its MAO inhibitory activity. Unlike selegiline, rasagiline has no amphetamine-like metabolites and its major metabolite, 1-(R)-aminoindan, has demonstrated favourable pharmacological activity in experimental studies. Rasagiline has shown significant beneficial effects as monotherapy in the treatment of early Parkinson's disease. Monotherapy with rasagiline 1 or 2 mg once daily significantly attenuated the worsening of symptoms, compared with placebo, in patients with early Parkinson's disease in a randomised, double-blind trial (n = 404). Furthermore, patients treated with rasagiline for 12 months had less functional decline than patients whose treatment was delayed for 6 months (n = 371). In patients with moderate-to-advanced disease receiving background therapy with levodopa and additional anti-parkinsonian medications (n = 1159), rasagiline 0.5 or 1 mg once daily reduced the daily 'off' time by 0.49-0.94 hours relative to that in placebo recipients in two randomised, double-blind trials. The efficacy of rasagiline 1 mg once daily was similar to entacapone 200 mg administered with each levodopa dose. Rasagiline was generally well tolerated in clinical trials as both monotherapy and when administered with other antiparkinsonian drugs. Adverse events with rasagiline were generally similar in frequency to those seen in placebo or entacapone recipients.     

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 Parkinson's 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.     

Lights and shadows on monoamine oxidase inhibition in neuroprotective pharmacological therapies

Playing a pivotal role in the metabolism of neurotransmitters in the central nervous system, the mitochondrial enzymes monoamine oxidases A and B (MAO A and B) have been for long studied as drug targets for neurodegenerative and neurological diseases. MAO inhibitors (MAOIs) are clinically used to treat Parkinson's disease and depression by blocking the degradation of neuroactive catecholamines and providing a symptomatic relief in the patients. More recent is the idea that the neuroprotective effect of MAOIs may result from the prevention of oxidative stress produced by the MAO reaction rather than being simply related to the inhibition of neurotransmitters degradation. Tranylcypromine and phenelzine are among the first developed MAOI drugs and have been used for years to treat depression. Their usage is now limited to cases of refractory depression because of their negative side effects, which are due to both the lack of MAO A/MAO B selectivity and the inhibition of other enzymes such as the drug-metabolizing cytochromes P450. Although the multi-target action of these MAOIs determines negative implications, the most newly developed compounds have improved properties not only for their specificity relatively to MAO A/MAO B selectivity but also because they function through multiple mechanisms that produce beneficial effects. In particular, safinamide, a MAO B selective inhibitor in clinical trials for Parkinson's disease, is neuroprotective by blocking the voltage-dependent Na+ and Ca2+ channels and the Ca2+-mediated glutamate release processes. Rasagiline is a drug used in combination with L-dopa in the treatment of parkinsonian patients and the metabolic products of its degradation exert neuroprotective effects. Moreover, rasagiline scaffold is used to design analogs by addition of pharmacophores that act on other neurological targets. This multi-target approach may prove successful in order to find new and more effective therapies for the complexity of neurodegenerative diseases.     

Rasagiline: A second-generation monoamine oxidase type-B inhibitor for the treatment of Parkinson's disease.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, and safety of rasagiline are reviewed. SUMMARY: Rasagiline is a novel, investigational propargylamine that irreversibly and selectively inhibits monoamine oxidase type B (MAO-B). Rasagiline demonstrates complete and selective inhibition of MAO-B and is at least five times more potent than selegiline. Unlike selegiline, which is metabolized to amphetamine derivatives, rasagiline is biotransformed to the nonamphetamine compound aminoindan. Clinical studies have revealed that rasagiline is associated with improved outcomes in patients with early Parkinson's disease (PD) and also reduces "off" time in patients with moderate to advanced PD with motor fluctuations. Rasagiline is rapidly absorbed by the gastrointestinal tract and readily crosses the blood-brain barrier. The optimal therapeutic dosage is 0.5-1 mg administered orally once daily. Rasagiline appears to be well tolerated, although elderly patients may be more prone to treatment-emergent adverse cardiovascular and psychiatric effects. At the recommended therapeutic dosage of up to 1 mg once daily, tyramine restriction is unnecessary. In addition to MAO-B inhibition, rasagiline has demonstrated neuroprotective properties in experimental laboratory models. The mechanisms whereby rasagiline exerts neuroprotective effects are multifactorial and include upregulation of cellular antioxidant activity and antiapoptotic factors. CONCLUSION: Rasagiline is an investigational selective and irreversible inhibitor of MAO-B that has demonstrated efficacy and safety for the treatment of PD. Whether rasagiline is associated with clinically significant neuroprotection is the subject of ongoing clinical trials.     

Rasagiline. Teva Pharmaceutical

Rasagiline is a selective and potent irreversible MAO(B) inhibitor which is under development by Teva for the treatment of neurological diseases. Rasagiline is in phase III trials in the US, Canada and Europe for Parkinson's disease (PD) and has completed phase II trials in Israel and Hungary. Teva planned to submit a filing in 2002 and expected to launch rasagiline in 2003. Lundbeck acquired European development and commercialization rights to rasagiline in November 1999 and, in September 2001, the company reported that it planned to file an NDA in 2003. In March 2002, analysts at Morgan Stanley Dean Witter predicted that H Lundbeck would make sales of rasagiline of DKr 100 million in 2003, rising to DKr 300 million in 2008. In the same month, launch was predicted in 2004/2005 for the PD indication, and 2005/2006 for the AD indication, by analysts at Deutsche Banc Alex Brown.     

Neuroprotection by rasagiline: a new therapeutic approach to Parkinson's disease?

Neuronal death in Parkinson's disease (PD) may originate from the reciprocal interactions of a restricted number of conditions, such as mitochondrial defects, oxidative stress and protein mishandling, which would favor a state of apoptotic cell death in the nigrostriatal pathway. The search for pharmacological treatments able to counteract the nigrostriatal degeneration, possibly by interfering with these phenomena, has recently raised considerable interest in rasagiline [R(+)-N-propargyl-1-aminoindan], a potent, selective, and irreversible inhibitor of monoamine oxidase B (MAO-B). Rasagiline, like selegiline, is a propargylamine, but is approximately 10 times more potent. Unlike selegiline, rasagiline is not metabolized to amphetamine and/or methamphetamine and is devoid of sympathomimetic activity. Numerous experimental studies, conducted both in vitro and in vivo, have shown that rasagiline possesses significant protective properties on neuronal populations. The pro-survival effects of the drug appear to be linked to its propargyl moiety, rather than to the inhibitory effect on MAO-B. Rasagiline's major metabolite, aminoindan--which possesses intrinsic neuroprotective activity--may also contribute to the beneficial effects of the parent compound. Rasagiline has been recently evaluated in early PD patients, with results that are consistent with slowing the progression of the disease. Therefore, the neuroprotective activity shown by the drug under experimental conditions may be reflected in the clinic, thus providing new perspectives for the treatment of PD.     

Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes

In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (MAO-B), (-)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. Rasagiline and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT.     

Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B

1. Rasagiline [N-propargyl-1R(+)-aminoindan], was examined for its monoamine oxidase (MAO) A and B inhibitor activities in rats together with its S(-)-enantiomer (TVP 1022) and the racemic compound (AGN-1135) and compared to selegiline (1-deprenyl). The tissues that were studied for MAO inhibition were the brain, liver and small intestine. 2. While rasagiline and AGN1135 are highly potent selective irreversible inhibitors of MAO in vitro and in vivo, the S(-) enantiomer is relatively inactive in the tissues examined. 3. The in vitro IC(50) values for inhibition of rat brain MAO activity by rasagiline are 4.43+/-0.92 nM (type B), and 412+/-123 nM (type A). The ED(50) values for ex vivo inhibition of MAO in the brain and liver by a single dose of rasagiline are 0.1+/-0.01, 0.042+/-0.0045 mg kg(-1) respectively for MAO-B, and 6.48+/-0.81, 2.38+/-0.35 mg kg(-1) respectively for MAO-A. 4. Selective MAO-B inhibition in the liver and brain was maintained on chronic (21 days) oral dosage with ED(50) values of 0.014+/-0.002 and 0.013+/-0.001 mg kg(-1) respectively. 5. The degree of selectivity of rasagiline for inhibition of MAO-B as opposed to MAO-A was similar to that of selegiline. Rasagiline was three to 15 times more potent than selegiline for inhibition of MAO-B in rat brain and liver in vivo on acute and chronic administration, but had similar potency in vitro. 6. These data together with lack of tyramine sympathomimetic potentiation by rasagiline, at selective MAO-B inhibitory dosage, indicate that this inhibitor like selegiline may be a useful agent in the treatment of Parkinson's disease in either symptomatic or L-DOPA adjunct therapy, but lack of amphetamine-like metabolites could present a therapeutic advantage for rasagiline.     

The essentiality of Bcl-2, PKC and proteasome-ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline

The anti-Parkinson drug, rasagiline, a irreversible propargyl possessing monoamine oxidase B inhibitor can protect neurons in vitro and in vivo from a variety of neurotoxic insults including SIN-1, glutamate, the parkinsonism inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, N-methyl-(R)-salsolinol and including beta amyloid protein. Recent studies have shown that rasagiline rapidly modulates intracellular signaling pathways involved in cell survival and death. Specifically rasagiline activates Bcl-2, Bcl-xl, protein kinase C (PKC) and reduces Bax in a variety of cells including PC-12 and neuroblastoma human dopamine derived SH-SY5Y cells. These enzymes play key roles in cellular events including modulation of apoptotic processes, neuronal plasticity and amyloid precursor protein processing. This pharmacological action of rasagiline is also associated with the prevention of the neurotoxin induced fall in mitochondrial membrane potential, opening of mitochondria permeability transition pore, activation of proteasome-ubiquitin complex, inhibition of cytochrome c release and prevention of caspase 3 activation, similar to the actions of cyclosporin A or Bcl-2 over expression in SH-SY5Y cells. Rasagiline and its various derivatives induces PKC dependent release of soluble amyloid precursor protein alpha and which is blocked by inhibitors of alpha-secretase, PKC and MAPK-dependent signaling. Structure-activity relationship with various propargyl containing derivatives of rasagiline including propargylamine itself has shown that the above described pharmacological action of these compounds resides in the propargylamine moiety. These results have provided a new understanding into the mechanism of neuroprotective actions of rasagiline and its anti-Alzheimer drug derivatives TV3326 and TV3279, which are relevant for therapy of Parkinson's disease, Alzheimer's disease and other neurodegenerative diseases.     

Characterization of the neuroprotective activity of rasagiline in cerebellar granule cells

Rasagiline (N-propargyl-1-R-aminoindan) is a new selective inhibitor of MAO-B which is in development for the treatment of Parkinson's disease. The aim of the present study was to evaluate the neuroprotective properties of rasagiline and characterize the mechanism by which it exerts its neuroprotective effect in cerebellar granule cells. Cerebellar granule cells were prepared from 7 to 8 days postnatal Sprague-Dawley rats and maintained in high K(+) (25 mM) medium. Rasagiline increased the survival of cerebellar granule cells treated with cytosine beta-D-arabinofuranoside (Ara-C), L-buthionine-(S,R)-sulfoximine (BSO) or glutamate (100 microM) but did not reduce cell death induced by transferring the cells to physiological K(+) concentration (5 mM) or by serum deprivation. Examination of different derivatives of rasagiline showed that the propargyl moiety is essential to the neuroprotective effect of these molecules, as the compound 1-R-aminoindan (a major metabolite of rasagiline) was devoid of neuroprotective effect in this model system and a rasagiline derivative with a double bond in place of the acetylenic propargyl triple bond was much less effective. The S(-)-enantiomer of rasagiline was also significantly less active than R(+)-rasagiline, as was 6-fluoro rasagiline. Addition of rasagiline (0.1-10 microM) to cerebellar granule cells grown in medium containing a physiological concentration of K(+) did not have an effect on neurite outgrowth as measured by synapsin expression level but increased the density of glial cell processes. The neuroprotective effects of rasagiline may include a direct action on the neurons through inhibition of neuronal death as well as an indirect effect mediated by the astrocytes.     

Cardiovascular responses to combined treatment with selective monoamine oxidase type B inhibitors and L-DOPA in the rat

BACKGROUND AND PURPOSE: Postural hypotension is a common side-effect of L-DOPA treatment of Parkinson's disease, and may be potentiated when L-DOPA is combined with selegiline, a selective inhibitor of monoamine oxidase B (MAO-B). Rasagiline is a new, potent and selective MAO-B inhibitor, which does not possess the sympathomimetic effects of selegiline. We have studied the effects of these selective MAO inhibitors, L-DOPA and dopamine on the cardiovascular system of the rat. EXPERIMENTAL APPROACH: Blood pressure and heart rate was measured in conscious rats following acute or chronic administration of rasagiline, selegiline and L-DOPA, by comparison with the selective MAO-A inhibitor clorgyline, or the MAO-A/B inhibitor tranylcypromine. Cardiovascular responses, catecholamine release, and modification of pressor response to dopamine were studied in pithed rats. KEY RESULTS: In conscious rats neither rasagiline nor selegiline caused significant potentiation of the effects of L-DOPA (50, 100, 150 mg.kg(-1)) on blood pressure or heart rate at doses which selectively inhibited MAO-B, but L-DOPA responses were potentiated by clorgyline and tranylcypromine. In rats treated twice daily for 8 days with L-DOPA and carbidopa, selegiline (5 mg.kg(-1)) but not rasagiline (0.2 mg.kg(-1)) caused a significant hypotensive response to L-DOPA and carbidopa, although both drugs caused similar inhibition of MAO-A and MAO-B. In pithed rats, selegiline but not rasagiline increased catecholamine release and heart rate, and potentiated dopamine pressor response at MAO-B selective dose. CONCLUSIONS AND IMPLICATIONS: The different responses to the two MAO-B inhibitors may be explained by the amine releasing effect of amphetamine metabolites formed from selegiline.     

Anti-apoptotic function of propargylamine inhibitors of type-B monoamine oxidase

In Parkinson's disease and other neurodegenerative diseases, (_- )deprenyl, an inhibitor of type B monoamine oxidase (MAO-B), has been proposed to protect or rescue declining neurons. However, clinical trials failed to confirm the neuroprotection, even though in vivo and in vitro studies suggested the possibilities. This paper describes the activities of propargylamine MAO-B inhibitors against apoptosis induced by an endogenous selective dopaminergic neurotoxin, N-methyl(R)salsolinol, in dopaminergic SH-SY5Y cells. A series of propargylamines were shown to suppress the apoptotic cascade; preventing collapse of mitochondrial membrane potential, activation of caspase 3 and fragmentation of nucleosomal DNA. Among propargylamines, (R)-N-propargyl1-aminoindan (rasagiline) was the most potent at preventing cell death. Rasagiline also prevented opening of permeability transition pore in insolated mitochondria. These results suggest that rasagiline and other propargylamines may regulate the apoptotic machinery in mitochondria and rescue or protect deteriorated neurons in neurodegenerative disorders.     

Effects of rasagiline, its metabolite aminoindan and selegiline on glutamate receptor mediated signalling in the rat hippocampus slice in vitro

Background

Rasagiline, a new drug developed to treat Parkinson's disease, is known to inhibit monoamine oxidase B. However, its metabolite R-(-)-aminoindan does not show this kind of activity. The present series of in vitro experiments using the rat hippocampal slice preparation deals with effects of both compounds on the pyramidal cell response after electric stimulation of the Schaffer Collaterals in comparison to selegiline, another MAO B inhibitor.

Method

Stimulation of the Schaffer Collaterals by single stimuli (SS) or theta burst stimulation (TBS) resulted in stable responses of pyramidal cells measured as population spike amplitude (about 1 mV under control SS conditions or about 2 mV after TBS).

Results

During the first series, this response was attenuated in the presence of rasagiline and aminoindan-to a lesser degree of selegiline-in a concentration dependent manner (5-50 ??M) after single stimuli as well as under TBS. During oxygen/glucose deprivation for 10 min the amplitude of the population spike breaks down by 75%. The presence of rasagiline and aminoindan, but rarely the presence of selegiline, prevented this break down. Following glutamate receptor mediated enhancements of neuronal transmission in a second series of experiments very clear differences could be observed in comparison to the action of selegiline: NMDA receptor, AMPA receptor as well as metabotropic glutamate receptor mediated increases of transmission were concentration dependently (0,3 - 2 ??M) antagonized by rasagiline and aminoindan, but not by selegiline. On the opposite, only selegiline attenuated k ainate receptor mediated increases of excitability. Thus, both monoamino oxidase (MAO) B inhibitors show attenuation of glutamatergic transmission in the hippocampus but interfere with different receptor mediated excitatory modulations at low concentrations.

Conclusions

Since aminoindan does not induce MAO B inhibition, these effects must be regarded as being independent from MAO B inhibition. The results provide strong evidence for a neuroprotective activity of rasagiline and aminoindan in concert with an extended clinical indication into the direction of other diseases like Alzheimer's disease or stroke.     

Neuroprotective effect of rasagiline, a selective monoamine oxidase-B inhibitor, against closed head injury in the mouse

The potential neuroprotective effects of rasagiline, N-propargyl-1R-aminoindan, a selective monoamine oxidase-B inhibitor and its inactive enantiomer TVP 1022, N-propargyl-1S-aminoindan were assessed against the sequelae of closed head injury in the mouse. Injury was induced in the left hemisphere under ether anaesthesia. Rasagiline (0.2 and 1 mg/kg) or TVP1022 (1 and 2 mg/kg) injected 5 min after injury accelerated the recovery of motor function and spatial memory and reduced the cerebral oedema by about 40-50%, (P < 0.01). The neuroprotective effects on motor function and spatial memory, but not on cerebral oedema, were prevented by scopolamine (0.2 mg/kg). Daily injection of rasagiline (1 mg/kg) from day 3 after injury accelerated the recovery of spatial memory but not motor function. Conclusions: Early administration of rasagiline or TVP1022 can reduce the immediate sequelae of brain injury. The mechanism of action does not appear to involve monoamine oxidase-B inhibition but could be mediated by the maintenance of cholinergic transmission in brain neurons.     

Spotlight on rasagiline in Parkinson's disease

Rasagiline (Azilect) is a novel, selective, irreversible second-generation inhibitor of monoamine oxidase type B (MAO-B). It is administered orally once daily and is approved in the US, Canada, Mexico, Israel and the EU for use as monotherapy and as adjunct therapy in the treatment of Parkinson's disease. Results of well designed clinical studies indicate that rasagiline is effective as initial monotherapy and improves Parkinson's symptomatology in patients with early Parkinson's disease. In addition, when administered in conjunction with levodopa, in patients with moderate to advanced disease and motor fluctuations, rasagiline reduces mean daily 'off' time and increases daily 'on' time without troublesome dyskinesias, compared with controls. Rasagiline is generally well tolerated as monotherapy and adjunctive therapy and is administered once daily. Thus, rasagiline, administered as a simple and convenient dosage regimen, is a well tolerated and effective option for monotherapy in patients with early Parkinson's disease and for adjunctive therapy in patients with moderate to advanced disease.     

Rasagiline: a review of its use in the management of Parkinson's disease

Rasagiline (Azilect) is a novel, selective, irreversible second-generation inhibitor of monoamine oxidase type B (MAO-B). It is administered orally once daily and is approved in the US, Canada, Mexico, Israel and the EU for use as monotherapy and as adjunct therapy in the treatment of Parkinson's disease.Results of well designed clinical studies indicate that rasagiline is effective as initial monotherapy and improves Parkinson's symptomatology in patients with early Parkinson's disease. In addition, when administered in conjunction with levodopa, in patients with moderate to advanced disease and motor fluctuations, rasagiline reduces mean daily 'off' time and increases daily 'on' time without troublesome dyskinesias, compared with controls. Rasagiline is generally well tolerated as monotherapy and adjunctive therapy and is administered once daily. Thus, rasagiline, administered as a simple and convenient dosage regimen, is a well tolerated and effective option for monotherapy in patients with early Parkinson's disease and for adjunctive therapy in patients with moderate to advanced disease.     

Binding of rasagiline-related inhibitors to human monoamine oxidases: a kinetic and crystallographic analysis

Monoamine oxidases A and B (MAO A and B) catalyze the degradation of neurotransmitters and represent drug targets for the treatment of neurodegenerative disorders. Rasagiline is an irreversible, MAO B-selective inhibitor that has been approved as a novel anti-Parkinson's drug. In this study, we investigate the inhibition of recombinant human MAO A and MAO B by several rasagiline analogues. Different substituents added onto the rasagiline scaffold alter the binding affinity depending on the position on the aminoindan ring and on the size of the substituent. Compounds with a hydroxyl group on either the C4 or the C6 atom inhibit both isozymes, whereas a bulkier substituent such as a carbamate is tolerated only at the C4 position. The 1.7 A crystal structure of MAO B in complex with 4-(N-methyl-N-ethyl-carbamoyloxy)-N-methyl-N-propargyl-1(R)-aminoindan shows that the binding mode is similar to that of rasagiline with the carbamate moiety occupying the entrance cavity space. 1(R)-Aminoindan, the major metabolic product of rasagiline, and its analogues reversibly inhibit both MAO A and MAO B. The crystal structure of N-methyl-1(R)-aminoindan bound to MAO B shows that its aminoindan ring adopts a different orientation compared to that of rasagiline.     

Disease modification in Parkinson's disease

Parkinson's disease (PD) is an age-related, progressive, multisystem neurodegenerative disorder resulting in significant morbidity and mortality, as well as a growing social and financial burden in an aging population. The hallmark of PD is loss of dopaminergic neurons of the substantia nigra pars compacta, leading to bradykinesia, rigidity and tremor. Current pharmacological treatment is therefore centred upon dopamine replacement to alleviate symptoms. However, two major problems complicate this approach: (i) motor symptoms continue to progress, requiring increasing doses of medication, which result in both short-term adverse effects and intermediate- to long-term motor complications; (ii) dopamine replacement does little to treat non-dopaminergic motor and non-motor symptoms, which are an important source of morbidity, including dementia, sleep disturbances, depression, orthostatic hypotension, and postural instability leading to falls. It is critical, therefore, to develop a broader and more fundamental therapeutic approach to PD, and major research efforts have focused upon developing neuroprotective interventions. Despite many encouraging preclinical data suggesting the possibility of addressing the underlying pathophysiology by slowing cell loss, efforts to translate this into the clinical realm have largely proved disappointing in the past. Barriers to finding neuroprotective or disease-modifying drugs in PD include a lack of validated biomarkers of progression, which hampers clinical trial design and interpretation; difficulties separating symptomatic and neuroprotective effects of candidate neuroprotective therapies; and possibly fundamental flaws in some of the basic preclinical models and testing. However, three recent clinical trials have used a novel delayed-start design in an attempt to overcome some of these roadblocks. While not examining markers of cell loss and function, which would determine neuroprotective effects, this trial design pragmatically tests whether earlier versus later intervention is beneficial. If positive (i.e. if an earlier intervention proves more effective), this demonstrates disease modification, which could result from neuroprotection or from other mechanisms. This strategy therefore provides a first step towards supporting neuroprotection in PD. Of the three delayed-start design clinical trials, two have investigated early versus later start of rasagiline, a specific irreversible monoamine oxidase B inhibitor. Each trial has supported, although not proven, disease-modifying effects. A third delayed-start-design clinical trial examining potential disease-modifying effects of pramipexole has unfortunately reportedly been negative according to preliminary presentations. The suggestion that rasagiline is disease modifying is made all the more compelling by in vitro and PD animal-model studies in which rasagiline was shown to have neuroprotective effects. In this review, we examine efforts to demonstrate neuroprotection in PD to date, describe ongoing neuroprotection trials, and critically discuss the results of the most recent delayed-start clinical trials that test possible disease-modifying activities of rasagiline and pramipexole in PD.     

Clinical pharmacology of rasagiline: a novel, second-generation propargylamine for the treatment of Parkinson disease

Rasagiline is a novel second-generation propargylamine that irreversibly and selectively inhibits monoamine oxidase type B (MAO-B). For the management of Parkinson disease (PD), rasagiline is efficacious across the span of PD stages ranging from monotherapy in early disease to adjunctive treatment in patients with advancing disease and motor fluctuations. Rasagiline completely and selectively inhibits MAO-B with a potency 5 to 10 times greater than selegiline. Unlike the prototype propargylamine selegiline, which is metabolized to amphetamine derivatives, rasagiline is biotransformed to aminoindan, a non-amphetamine compound. Rasagiline is well tolerated with infrequent cardiovascular or psychiatric side effects, and at the recommended therapeutic dose of up to 1 mg once daily, tyramine restriction is unnecessary. In addition to MAO-B inhibition, the propargylamine chain also confers dose-related antioxidant and antiapoptotic effects, which have been associated with neuroprotection in multiple experimental models. Thus, in addition to symptomatic benefits, rasagiline offers the promise of clinically relevant neuroprotection.     

Crystal structures of monoamine oxidase B in complex with four inhibitors of the N-propargylaminoindan class

Monoamine oxidase B (MAO B) is an outer mitochondrial membrane enzyme that catalyzes the oxidation of arylalkylamine neurotransmitters. The crystal structures of MAO B in complex with four of the N-propargylaminoindan class of MAO covalent inhibitors (rasagiline, N-propargyl-1(S)-aminoindan, 6-hydroxy-N-propargyl-1(R)-aminoindan, and N-methyl-N-propargyl-1(R)-aminoindan) have been determined at a resolution of better than 2.1 A. Rasagiline, 6-hydroxy-N-propargyl-1(R)-aminoindan, and N-methyl-N-propargyl-1(R)-aminoindan adopt essentially the same conformation with the extended propargyl chain covalently bound to the flavin and the indan ring located in the rear of the substrate cavity. N-Propargyl-1(S)-aminoindan binds with the indan ring in a flipped conformation with respect to the other inhibitors, which causes a slight movement of the Tyr326 side chain. Four ordered water molecules are an integral part of the active site and establish H-bond interactions to the inhibitor atoms. These structural studies may guide future drug design to improve selectivity and efficacy by introducing appropriate substituents on the rasagiline molecular scaffold.