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.
Original language | English |
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Pages (from-to) | 7911-9 |
Number of pages | 9 |
Journal | Journal of Medicinal Chemistry |
Volume | 54 |
Issue number | 22 |
DOIs | |
Publication status | Published - 24 Nov 2011 |
Keywords
- Animals
- Benzamides
- Binding, Competitive
- CHO Cells
- Cricetinae
- Cricetulus
- Cyclic AMP
- Drug Partial Agonism
- HEK293 Cells
- Humans
- Ligands
- Models, Molecular
- Piperazines
- Protein Multimerization
- Radioligand Assay
- Receptors, Dopamine D2
- Signal Transduction
- Structure-Activity Relationship
- Swine
- Triazoles