N-(4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with functionalized linking chains as high affinity and enantioselective D3 receptor antagonists

Abstract

In the present report, the D3 receptor pharmacophore is modified in the 2,3-diCl- and 2-OCH(3)-phenylpiperazine class of compounds with the goal to improve D3 receptor affinity and selectivity. This extension of structure-activity relationships (SAR) has resulted in the identification of the first enantioselective D3 antagonists (R- and S-22) to be reported, wherein enantioselectivity is more pronounced at D3 than at D2, and that a binding region on the second extracellular loop (E2) may play a role in both enantioselectivity and D3 receptor selectivity. Moreover, we have discovered some of the most D3-selective compounds reported to date that show high affinity (K(i) = 1 nM) for D3 and approximately 400-fold selectivity over the D2 receptor subtype. Several of these analogues showed exquisite selectivity for D3 receptors over >60 other receptors, further underscoring their value as in vivo research tools. These lead compounds also have appropriate physical characteristics for in vivo exploration and therefore will be useful in determining how intrinsic activity at D3 receptors tested in vitro is related to behaviors in animal models of addiction and other neuropsychiatric disorders.

Figure 1

X-ray crystal structure of S-22. Displacement ellipsoids are at the 50% level. For clarity only one of the four independent molecules in the asymmetric unit is shown.

Scheme 1

Synthesis of 5-Iodo-heterobiaryl Synthonsa ^aReagents and conditions: (a) I₂, EtOH, NaIO₃, H₂SO₄, (b) HCl, Zn, (c) EtOH, KOH, (d) 10M HCl, (e) N(t-Bu)₄I, K₂CO₃

Scheme 2

Synthesis of Compounds 17–37a ^aReagents and conditions: (a) CDI, THF (Method A); (b) SOCl₂ (Method B)