title: Synthesis and pharmacological evaluation of dual acting ligands targeting the adenosine A2A and dopamine D2 receptors for the potential treatment of Parkinson's disease.
abstract: A relatively new strategy in drug discovery is the development of dual acting ligands. These molecules are potentially able to interact at two orthosteric binding sites of a heterodimer simultaneously, possibly resulting in enhanced subtype selectivity, higher affinity, enhanced or modified physiological response, and reduced reliance on multiple drug administration regimens. In this study, we have successfully synthesized a series of classical heterobivalent ligands as well as a series of more integrated and "drug-like" dual acting molecules, incorporating ropinirole as a dopamine D2 receptor agonist and ZM 241385 as an adenosine A2A receptor antagonist. The best compounds of our series maintained the potency of the original pharmacophores at both receptors (adenosine A2A and dopamine D2). In addition, the integrated dual acting ligands also showed promising results in preliminary blood-brain barrier permeability tests, whereas the classical heterobivalent ligands are potentially more suited as pharmacological tools.
authors.affiliation: Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Manuela
authors.initials: M
authors.lastname: Jörg
authors.forename: Lauren T
authors.initials: LT
authors.lastname: May
authors.forename: Frankie S
authors.initials: FS
authors.lastname: Mak
authors.forename: Kiew Ching K
authors.initials: KC
authors.lastname: Lee
authors.forename: Neil D
authors.initials: ND
authors.lastname: Miller
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
authors.forename: Ben
authors.initials: B
authors.lastname: Capuano
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001812:Blood-Brain Barrier; D016466:CHO Cells; D003412:Cricetulus; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D008024:Ligands; D017448:Receptors, Dopamine D2