Development of a Bivalent Dopamine D-2 Receptor Agonist

作者：Kuehhorn Julia; Goetz Angela; Huebner Harald; Thompson Dawn; Whistler Jennifer; Gmeiner Peter^*

来源：Journal of Medicinal Chemistry, 2011, 54(22): 7911-7919.

DOI：10.1021/jm2009919

Bivalent D-2 agonists may function as useful molecular probes for the discovery of novel neurological therapeutics. On the basis of our recently developed bivalent dopamine D-2 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 D-2 agonists substantially inhibiting cAMP accumulation and inducing D-2 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.

• 出版日期2011-11-24