title: Development of a bivalent dopamine D₂ receptor agonist.
abstract: Bivalent D₂ agonists may function as useful molecular probes for the discovery of novel neurological therapeutics. On the basis of our recently developed bivalent dopamine D₂ receptor antagonists of type 1, the bivalent agonist 2 was synthesized when a spacer built from 22 atoms was employed. Compared to the monovalent control compound 6 containing a capped spacer, the bis-aminoindane derivative 2 revealed substantial steepening of the competition curve, indicating a bivalent binding mode. Dimer-specific Hill slopes were not a result of varying functional properties because both the dopaminergic 2 and the monovalent control agent 6 proved to be D₂ agonists substantially inhibiting cAMP accumulation and inducing D₂ receptor internalization. Investigation of the heterobivalent ligands 8 and 9, containing an agonist and a phenylpiperazine-based antagonist pharmacophore, revealed moderate steepening of the displacement curves and antagonist to very weak partial agonist properties.
authors: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany.
authors: Julia
authors: J
authors: Kühhorn
authors: Angela
authors: A
authors: Götz
authors: Harald
authors: H
authors: Hübner
authors: Dawn
authors: D
authors: Thompson
authors: Jennifer
authors: J
authors: Whistler
authors: Peter
authors: P
authors: Gmeiner
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D054333:Drug Partial Agonism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D055503:Protein Multimerization; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013552:Swine; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001549:Benzamides; D008024:Ligands; D010879:Piperazines; D017448:Receptors, Dopamine D2; D014230:Triazoles; D000242:Cyclic AMP