title: 1-substituted apomorphines as potent dopamine agonists.
abstract: A novel set of 1-substituted apomorphines as dopaminergic agonists were synthesized according to our new strategy employing the acid-catalyzed rearrangement of diversely functionalized 5β-substituted-6-demethoxythebaines. The activities of new compounds for dopamine receptors subtypes were evaluated using HEK293 based stable cell lines expressing D1, D2L or D3 receptor subtypes. All studied compounds had affinities in nanomolar range for D2L and D3 receptors and the change of the nature of substituent in position 1 had only moderate effect. D1 receptors were sensitive to the introduction of the 4-OH-benzyl function resulting in an increased affinity. The small hydrophilic group (hydroxymethyl) highly reduced the agonist affinity and potency thereby increasing subtype selectivity. This strategy for selective modulation of affinities and potencies of 1-substituted apomorphines gives essential hints for future design of subtype selective dopaminergic ligands.
authors.affiliation: Institute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu, Estonia.
authors.forename: Reet
authors.initials: R
authors.lastname: Reinart-Okugbeni
authors.forename: Argo
authors.initials: A
authors.lastname: Vonk
authors.forename: Ain
authors.initials: A
authors.lastname: Uustare
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Gyulai
authors.forename: Attila
authors.initials: A
authors.lastname: Sipos
authors.forename: Ago
authors.initials: A
authors.lastname: Rinken
mesh_terms: D001058:Apomorphine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011954:Receptors, Dopamine / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018491:Dopamine Agonists; D011954:Receptors, Dopamine; D001058:Apomorphine