Novel Bivalent Ligands
for D2/D3 Dopamine Receptors:
Significant Cooperative Gain in D2 Affinity and Potency
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Abstract
This report describes development of a series of novel
bivalent
molecules with a pharmacophore derived from the D2/D3 agonist 5-OH-DPAT.
The 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 <b>11d</b> and <b>14b</b>) as compared to monovalent 5-OH-DPAT (<i>K</i><sub>i</sub>; 2.5 and 2.0 vs 59 nM for <b>11d</b> and <b>14b</b> vs 5-OH-DPAT, respectively). The functional
potency of <b>11d</b> and <b>14b</b> indicated a 24- and
94-fold increase in potency at the D2 receptor as compared to 5-OH-DPAT
(EC<sub>50</sub>; 1.7 and 0.44 vs 41 nM for <b>11d</b> and <b>14b</b> vs 5-OH-DPAT, respectively). These are the most potent
bivalent agonists for the D2 receptor known to date. This synergism
is consonant with cooperative interaction at the two orthosteric binding
sites in the homodimeric receptor