Die adenosien A1- en A2A-reseptoraffiniteit van ’n reeks 3,4-dihidropirimidoon-analoë

Abstract

Parkinson se siekte is ’n komplekse neurodegeneratiewe siektetoestand. Huidige behandeling van dié siekte is slegs op simptomatiese verligting gemik, sonder dat die siekteverloop vertraag of gestop word. Sedert die ontdekking dat adenosien A1- en A2A- reseptore potensiële geneesmiddelteikens vir die behandeling van Parkinson se siekte is, het verskeie navorsingsgroepe gepoog om adenosienantagoniste te identifiseer. Benewens die bevinding dat adenosien A2A-reseptorantagoniste die motoriese simptome verminder wat met Parkinson se siekte gepaardgaan, is hulle potensieel ook neurobeskermend. Dit is dus moontlik dat verdere neurodegenerasie met sulke middels voorkom kan word. Verder kan die antagonisme van adenosien A1-reseptore die kognitiewe defekte, wat met Parkinson se siekte geassosieer word, moontlik verlig. Dualistiese antagonisme van adenosien A1- en A2A-reseptore kan dus van groot waarde wees, aangesien dit die moontlikheid bied om beide die motoriese sowel as die kognitiewe verswakking van Parkinson se siekte te behandel. Dit is vasgestel dat ’n reeks 1,4-dihidropiridienderivate affiniteit vir die adenosien A1- en A2A-reseptore besit en gegrond op hierdie bevinding, is die struktureelverwante 3,4-dihidropirimidoon-analoë as adenosien A1- en A2A- reseptorantagoniste in hierdie studie ondersoek. Oor die algemeen is gevind dat die 3,4-dihidropirimidoon-analoë swak adenosien A2A-reseptoraffiniteit besit, maar dat hul affiniteit vir die adenosien A1-reseptor meer belowende resultate opgelewer het, met dissosiasiekonstante-waardes in die lae mikromolêre gebied. Die p-bromofenielgesubstitueerde dihidropirimidoon (6b) het die beste adenosien A1-reseptoraffiniteit getoon met ’n Ki-waarde van 7.39 μM. Gevolglik kan dié 3,4-dihidropirimidoon-analoog as leidraadverbinding gebruik word vir die ontwikkeling van nuwe adenosien A1- reseptorantagoniste, alhoewel verdere strukturele veranderinge nodig is om die adenosien A2A-affiniteit te verbeter ten einde ’n kliniese lewensvatbare kandidaat vir die behandeling van Parkinson se siekte te verkry

Parkinson’s disease is a complex neurodegenerative condition with current treatment only focussed on symptomatic therapy that does not slow or stop the progression of the disease. Since the discovery that adenosine A1 and A2A receptors are potential drug targets for the therapy of Parkinson’s disease, various research groups have attempted to identify adenosine antagonists. So the possibility exists that the administration of an adenosine A2A receptor antagonist may prevent further neurodegeneration. Furthermore, the antagonism of adenosine A1 receptors has the potential of treating Parkinson’s disease-associated cognitive deficits. Therefore, dual antagonism of adenosine A1 and A2A receptors would be of great benefit since this would potentially treat both the motor as well as the cognitive impairment associated with Parkinson’s disease. Based on the observation that a series of 1,4-dihydropyridine derivatives possess adenosine A1 and A2A receptor affinity, the current study investigated the potential of the structurally related 3,4-dihydropyrimidone analogues as adenosine A1 and A2A receptor antagonists. Overall, the 3,4-dihyropyrimidone analogues were found to possess weak affinity for the adenosine A2A receptor, but more promising adenosine A1 receptor affinity was found, ranging in the low micromolar range. Among the investigated compounds, the p-bromophenyl substituted dihydropyrimidone (6b) possesses the best adenosine A1 receptor affinity with a Ki value of 7.39 µM. In conclusion, this 3,4-dihydropyrimidone derivative can be used as a lead for the design of novel adenosine A1 receptor antagonists, although further structural modifications are required to enhance the adenosine A2A receptor affinity before a clinically viable candidate will be available as potential treatment of Parkinson’s disease