The synthesis and evaluation of imidazopyridines as adenosine receptor antagonists

Abstract

Alzheimer’s disease (AD) is the most common occurring neurodegenerative disorder worldwide and includes deficiencies in memory and cognitive impairment. Both the hippocampus and cortex are important neuronal areas in the regulation of cognitive function, while the hippocampus is central in memory processing. Treatment that is currently available aims at restoring the acetylcholine imbalance and includes antioxidants, cholinesterase inhibitors and psychotropic drugs for the symptomatic treatment of AD. These drugs, however, fail to prevent further disease progression and neurodegeneration from occurring, therefore necessitating the need to explore and develop alternative treatments. Parkinson’s disease (PD) is a chronic, age-related neurodegenerative disorder that may be characterised pathologically by the loss of dopaminergic neurons in the nigrostriatal pathway, causing dopamine in the striatum to decrease. Thus far no curative treatment for the disorder exists with the only available treatment aiming to restore the dopamine deficiencies in the brain. L-dopa remains the gold standard treatment of PD, whilst dopamine agonists, selective monoamine oxidase-B inhibitors, and anticholinergic drugs are used for the symptomatic treatment of PD. None of the treatment currently available slow, terminate or prevent the neurodegeneration from occurring, thus the development of disease modifying drugs are essential. Adenosine plays an important role in neurodegenerative disorders such as AD and PD. There are four receptor subtypes of adenosine and they are classified as A1, A2A, A2B, and A3. The adenosine A1 receptors are important for cognitive function and are found copiously throughout the hippocampus and cortex. In turn the adenosine A2A receptors are highly expressed in the striatum and play an important role in motor function and neuroprotection. In the case of AD and PD, adenosine A2A receptor antagonists have neuroprotective properties by preventing β-amyloid neurotoxicity in AD and protecting nigrostriatal dopaminergic neurons from neurodegeneration in PD. Furthermore, selective adenosine A1 receptor antagonists may improve cognitive functions due to their expression in the hippocampus and cortex and selective adenosine A2A receptor antagonists may also improve motor function due to the expression of the adenosine A2A receptors in the striatum. Depression is a common neuropsychiatric symptom in both AD and PD and remains inadequately treated with current drugs available. Adenosine A2A receptor antagonists have displayed antidepressant effects in rodent models of depression and may find therapeutic value to improve depressive symptoms. Therefore development of non-selective adenosine receptor antagonists are attractive for the treatment of both AD and PD as they improve the cognitive and motor function, prevent further neurodegeneration and improve the depressive symptoms in both disorders. Previous research has shown that bicyclic 6:5-fused heteroaromatic compounds with two N-atoms have variable degrees of adenosine A1 antagonistic activity. Prompted by this a pilot study was undertaken, where imidazo[1,2-α]pyridine analogues were synthesised, characterised and evaluated for their adenosine A1 and A2 antagonistic activity as possible treatment agents for AD and PD. Radioligand binding studies were performed to determine the adenosine binding affinities and the most promising adenosine A1 receptor analogue was subjected to a GTP shift assay to determine whether or not the compound has agonistic or antagonistic functionality. Imidazo[1,2-α]pyridine analogues (4a–i) were synthesised by means of a modified catalyst-and-solvent-free method by reacting cyclohexyl isocyanide, 2-aminopyridine and the appropriate aldehyde at a suitable temperature. Compounds 1 and 3a–e were obtained commercially and used to compare the effect of substitution on position C2 alone as well as position C2 in combination with position C3 on adenosine A1 and A2A receptor affinity. Imidazo[1,2-α]pyridine, the parent scaffold, was found devoid of affinity for the adenosine A1 and A2A receptors. The influence of substitution on position C2 showed no improvement for either adenosine A1 or A2A receptor affinity. The addition of an amino or a cyclohexylamino group to position C3 also showed no improvement of adenosine A1 or A2A receptor affinity. Surprisingly para-substitution on the phenyl ring at position C2 in combination with a cyclohexylamino group at position C3 led to adenosine A1 receptor affinity in the low micromolar range with compound 4d (para-methyl) showing the highest affinity for the adenosine A1 receptor with a Ki value of 2.06 μM. Compound 4d behaved as an adenosine A1 receptor antagonist in the GTP shift assay performed with rat whole brain membranes expressing adenosine A1 receptors. This pilot study concludes that para-substituted 3-cyclohexylamino-2-phenylimidazo[ 1,2-α]pyridine analogues represent an interesting scaffold to investigate further structure-activity relationships in the design of novel imidazo[1,2-α]pyridine based adenosine A1 receptor antagonists for the treatment of neurodegenerative disorders such as AD and PD