Development of a bivalent dopamine D(2) receptor agonist.

Article Details

Citation

Kuhhorn J, Gotz A, Hubner H, Thompson D, Whistler J, Gmeiner P

Development of a bivalent dopamine D(2) receptor agonist.

J Med Chem. 2011 Nov 24;54(22):7911-9. doi: 10.1021/jm2009919. Epub 2011 Oct 31.

PubMed ID
21999579 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
HaloperidolDopamine D2 receptorKi (nM)1.5N/AN/ADetails
HaloperidolDopamine D2 receptorKi (nM)1.1N/AN/ADetails
HaloperidolDopamine D3 receptorKi (nM)6.3N/AN/ADetails