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Novel bivalent ligands for D2/D3 dopamine receptors: Significant co-operative gain in D2 affinity and potency.

ABSTRACT: This report describes development of a series of novel bivalent molecules with a pharmacophore derived from the D2/D3 agonist 5-OH-DPAT. Spacer length in the bivalent compounds had a pronounced influence on affinity for D2 receptors. A 23-fold increase of D2 affinity was observed at a spacer length of 9 or 10 (compounds 11d and 14b) compared to monovalent 5-OH-DPAT (Ki; 2.5 and 2.0 vs. 59 nM for 11d and 14b vs. 5-OH-DPAT, respectively). Functional potency of 11d and 14b indicated a 24- and 94-fold increase in potency at the D2 receptor compared to 5-OH-DPAT (EC50; 1.7 and 0.44 vs. 41 nM for 11d and 14b vs. 5-OH-DPAT, respectively). These are the most potent bivalent agonists for D2 receptor known to date. This synergism is consonant with cooperative interaction at the two orthosteric binding sites in the homodimeric receptor.

SUBMITTER: Gogoi S

PROVIDER: S-EPMC3530844 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Novel bivalent ligands for D2/D3 dopamine receptors: Significant co-operative gain in D2 affinity and potency.

Gogoi Sanjib S Biswas Swati S Modi Gyan G Antonio Tamara T Reith Maarten E A ME Dutta Aloke K AK

ACS medicinal chemistry letters 20121001 12

This report describes development of a series of novel bivalent molecules with a pharmacophore derived from the D2/D3 agonist 5-OH-DPAT. Spacer length in the bivalent compounds had a pronounced influence on affinity for D2 receptors. A 23-fold increase of D2 affinity was observed at a spacer length of 9 or 10 (compounds 11d and 14b) compared to monovalent 5-OH-DPAT (Ki; 2.5 and 2.0 vs. 59 nM for 11d and 14b vs. 5-OH-DPAT, respectively). Functional potency of 11d and 14b indicated a 24- and 94-fo ...[more]

PMID: 23275802

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