Design and Synthesis of [(2,3-Dichlorophenyl)piperazin-1-yl]alkylfluorenylcarboxamides as Novel Ligands Selective for the Dopamine D₃Receptor Subtype

Abstract

The dopamine D3 receptor subtype has been recently targeted as a potential neurochemical modulator of the behavioral actions of psychomotor stimulants, such as cocaine. However, definitive behavioral investigations have been hampered by the lack of highly selective D3 agonists and antagonists. In an attempt to design a novel class of D3 ligands with which to study this receptor system, a series of chemically divergent compounds that possessed various structural features that exist within several classes of reputed D3 agents was screened and compared to the recently reported NGB 2904 (58b). On the basis of these results, a novel series of compounds was designed that included functional moieties that were required for high-affinity and selective binding to D3 receptors. All the compounds in this series included an aryl-substituted piperazine ring, a varying alkyl chain linker (C3-C5), and a terminal aryl amide. The compounds were synthesized and evaluated in vitro for binding in CHO cells transfected with human D2, D3, or D4 receptor cDNAs. D3 binding affinities ranged from K(i) = 1.4 to 1460 nM. The most potent analogue in this series, 51, demonstrated a D3/D2 selectivity of 64 and a D3/D4 selectivity of 1300. Structure-activity relationships for this class of ligands at D3 receptors will provide new leads toward the development of highly selective and potent molecular probes that will prove useful in the elucidation of the role D3 receptors play in the psychomotor stimulant and reinforcing properties of cocaine.

Novel Heterocyclic Trans Olefin Analogues of N-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butyl}arylcarboxamides as Selective Probes with High Affinity for the Dopamine D3 Receptor

“…However, at the D2 receptor, the 2-iodo derivative 13 (K i ) 10.6 nM) showed a higher binding affinity than the 3-iodo benzamide 14 (K i ) 28.1 nM) and 4-iodo ligand 15 (K i ) 35.4 nM). The nitro derivatives (21)(22)(23) and the methoxylated ligands (16)(17)(18) exhibited similar SAR dependence on the position of substituent on the phenyl ring as the iodo-benzamides (13)(14)(15) at the D2 receptor. This effect was most pronounced for the methoxylated derivatives, wherein the 4-methoxy analogue 18 had a 10-fold lower affinity at the D2 receptor than the 2-methoxy ligand 16.…”

“…15,17 As depicted in Scheme 1, the N-phthalimido-protected trans-butenyl bromide 4 was linked to 2,3-dichlorophenylpiperazine. Deprotection of the intermediate 5 to the primary amine 6 was achieved by treatment with hydrazine.…”

A Series of 18F‐Labelled Pyridinylphenyl Amides as Subtype‐Selective Radioligands for the Dopamine D3 Receptor

“…[3,[17][18][19][20][21] Most of these studies were based on D3-selective lead compounds such as BP 897 (1), FAUC 346 (2), CJB 090 (3 a), or NGB 2904 (4). [6,[22][23][24] In 1999, BP 897 received great attention as it was first reported to be effective in the treatment of cocaine abuse.…”

18F‐Labeled FAUC 346 and BP 897 Derivatives as Subtype‐Selective Potential PET Radioligands for the Dopamine D3 Receptor

“…[17] 4-Phenylpiperazines can be regarded as a privileged GPCRbinding structure. [18] This class has been the subject of chemical optimization and thorough pharmacological investigation [19][20][21][22][23][24] when FAUC 346 (2 a) proved to be a high affinity (K i = 0.23 nm), potent (EC 50 = 1.5 nm) and highly selective D3 partial agonist (~50 % maximal intrinsic activity). On the other hand, the 2,3-dichlorophenyl analogue FAUC 365 turned out to act as a neutral antagonist with subnanomolar affinity (K i = 0.50 nm) and very high subtype selectivity (~7200 versus D2).…”