7-hydroxy-2-n-n-dipropylaminotetralin--(r)-isomer and Parkinson-Disease

Aiming to discover dual-acting β2 adrenergic/dopamine D2 receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic β2 receptor and substantial G protein-promoted activation at the D2 receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a β2 adrenergic antagonist/D2 receptor agonist with Ki values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders.

Topics: Adrenergic beta-2 Receptor Agonists; Animals; Benzoxazines; CHO Cells; Cricetulus; Dopamine Agonists; Drug Discovery; HEK293 Cells; Humans; Models, Molecular; Parkinson Disease; Polypharmacology; Receptors, Adrenergic, beta-2; Receptors, Dopamine D2

Here we report structure-activity relationship study of a novel hybrid series of compounds where structural alteration of aromatic hydrophobic moieties connected to the piperazine ring and bioisosteric replacement of the aromatic tetralin moieties were carried out. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors with tritiated spiperone to evaluate inhibition constants (K(i)). Functional activity of selected compounds in stimulating GTPgammaS binding was assessed with CHO cells expressing human D2 receptors and AtT-20 cells expressing human D3 receptors. SAR results identified compound (-)-24c (D-301) as one of the lead molecules with preferential agonist activity for D3 receptor (EC(50) (GTP gamma S); D3 = 0.52 nM; D2/D3 (EC(50)): 223). Compounds (-)-24b and (-)-24c exhibited potent radical scavenging activity. The two lead compounds, (-)-24b and (-)-24c, exhibited high in vivo activity in two Parkinson's disease (PD) animal models, reserpinized rat model and 6-OHDA induced unilaterally lesioned rat model. Future studies will explore potential use of these compounds in the neuroprotective therapy for PD.

Topics: Animals; Antiparkinson Agents; Benzothiazoles; CHO Cells; Cricetinae; Cricetulus; Disease Models, Animal; Free Radical Scavengers; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Isoquinolines; Locomotion; Mice; Parkinson Disease; Radioligand Assay; Rats; Receptors, Dopamine D2; Receptors, Dopamine D3; Reserpine; Structure-Activity Relationship; Thiazoles