Magic bullets or novel multimodal drugs with various CNS targets for Parkinson's disease?

Sirs

Schapira et al. recently published an excellent overview of therapeutic targets for Parkinson's disease (PD)1. Traditional drug design efforts optimize drug specificity against one selected target. Disappointingly, such 'magic bullet' drugs for CNS disorders, including PD and Alzheimer's disease (AD), have not been realized. Transcriptomics, proteomic profiling and genetic analyses indicate that PD is polyaetiological in origin, with multifactorial processes leading to neuronal death: any one of which can initiate neurodegenerative cascades. Braak's group² suggests that PD manifests in different stages, beginning with alterations in anterior olfactory structures and loss of smell, then initial subtle and subsequent increasingly severe changes in the substantia nigra and other nuclei of the basal midbrain and forebrain. Such changes result in a predisposition to depression among other neurological deficits associated with PD. In the final stages, lesions occur in the prefrontal cortex, with increasing cholinergic neuronal degeneration and onset of dementia. Thus, an emerging drug design concept for PD and AD therapeutics is to develop ligands that modulate the multiple drug targets available in these disorders. In this commentary, we present examples of novel multimodal drugs with various CNS targets (Fig. 1) that are in development for symptomatic and possibly neuroprotective–neurorescue treatment of PD³, which were not discussed by Schapira et al.

Figure 1: The structures of neuroprotective multifunctional drugs ladostigil and M30 depicting their derivation from monoamine oxidase (MAO) B inhibitor, rasagiline and iron chelator-radical scavenger, VK 28.

Ladostigil possesses the acetylcholinesterase and butyrlcholinesterase inhibitor moiety, carbamate and the MAO inhibitory and neuroprotective propargyl moiety. M30 has the iron-chelating pharmacophore moiety of VK 28 and the MAO inhibitory and neuroprotective propargyl moiety.

Ladostigil (TV3326; clinical Phase IIa) is one example of a multimodal drug for the treatment of AD and Lewy body disease (LBD). Ladostigil incorporates a carbamate moiety, which is associated with cholinesterase inhibition, into the pharmacophore of rasagiline (Azilect; Teva Pharmaceuticals). The carbamate moiety in ladostigil results in the inhibition of acetylcholinesterase and butyrylcholinesterase, whereas its propargylamine moiety is responsible for brain-selective monoamine oxidase (MAO) A and B inhibition, and interferes with the regulative processing of amyloid precursor protein. Ladostigil also possesses the in vitro and in vivo neuroprotection–neurorescue mechanisms associated with the propargylamine moiety similar to rasagiline^4,5. Preclinical studies show that ladostigil has antidepressant, anti-PD and anti-AD activities⁶, and clinical development is planned for AD, LBD and PD dementia.

Other multifunctional drug examples include the brain-permeable iron chelator and MAOA/B inhibitor M30, and the dual adenosine A_2A antagonists and brain MAOB inhibitors. One major pathology of PD is the accumulation of iron in the substantia nigra pars compacta, which contributes to oxidative-stress-associated toxicity⁷. Interestingly, similar iron accumulation patterns also occur in 6 hydroxydopamine and MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) parkinsonian models, whereby iron chelators attenuate the neurotoxicity of these agents. M30, currently undergoing development similar to ladostigil, possesses the MAO inhibitory and neuroprotective propargylamine moiety in the pharmacophore of the brain-permeable iron chelator VK 28. M30 and VK 28 prevents 6 hydroxydopamine and MPTP neurotoxicity. As a potent MAOA and MAOB inhibitor, M30 (unlike VK 28, which lacks MAO-inhibitor activity) increases brain levels of monoamine neurotransmitters. M30 may possess antidepressant activity that is due to MAOA inhibition, similar to non-selective MAO inhibitors and MAOA-selective inhibitors. In addition, the propargylamine moiety of M30 confers neuroprotection and neurorescue properties that ostensibly involve the regulation of the mitochondrial BCL-2 family of proteins and the activation of tyrosine kinase receptor signalling pathways, which is similar to rasagline⁸.

In PD, dual mechanistic inhibition of MAOB and adenosine A_2A receptor antagonism may offer another novel therapeutic approach to prevent neuronal cell death. Studies with KW 6002, a potent A_2A receptor antagonist undergoing clinical trials, and (E)-8-(3-chlorostyryl)caffeine (CSC) show that both compounds are neuroprotective in the MPTP mouse model⁹. Similar compounds tested showed significant MAOB inhibition, which suggests that the neuroprotective properties of KW 6002 and CSC may partly be due to MAOB inhibition in the brain in synergy with A₂A receptor antagonism^10,11.

The development of multifunctional drugs is not limited to PD and AD; this approach offers an exciting new concept with similar applications in drug development for treatment of depressive illness, schizophrenia, cardiovascular diseases, AIDS and cancer¹².