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.
Original language | English (US) |
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Pages (from-to) | 7911-7919 |
Number of pages | 9 |
Journal | Journal of Medicinal Chemistry |
Volume | 54 |
Issue number | 22 |
DOIs | |
State | Published - Nov 24 2011 |
Externally published | Yes |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery