Heterocyclic analogues of N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides with functionalized linking chains as novel dopamine D3 receptor ligands: potential substance abuse therapeutic agents.
Dopamine D3 receptor antagonists and partial agonists have been shown to modulate drug-seeking effects induced by cocaine and other abused substances. Compound 6 [PG01037, (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-trans-but-2-enyl)-4-pyridine-2-ylbenzamide)] and related analogues are currently being evaluated in animal models of drug addiction. In these studies, a discrepancy between in vitro binding affinity, in vivo occupancy, and behavioral potency has been observed. The purpose of this study was to examine (1) modifications of the 2-pyridylphenyl moiety of 6 and (2) hydroxyl, acetyl, and cyclopropyl substitutions on the butylamide linking chain systematically coupled with 2-fluorenylamide or 2-pyridylphenylamide and 2-methoxy- or 2,3-dichloro-substituted phenylpiperazines to measure the impact on binding affinity, D2/D3 selectivity, lipophilicity, and function. In general, these modifications were well tolerated at the human dopamine D3 (hD3) receptor (Ki = 1-5 nM) as measured in competition binding assays. Several analogues showed >100-fold selectivity for dopamine D3 over D2 and D4 receptors. In addition, while all the derivatives with an olefinic linker were antagonists, in quinpirole-stimulated mitogenesis at hD3 receptors, several of the hydroxybutyl-linked analogues (16, 17, 21) showed partial agonist activity. Finally, several structural modifications reduced lipophilicities while retaining the desired binding profile.
Medicinal Chemistry Section, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, Maryland 21224, USA.
Peter
P
Grundt
Katherine M
KM
Prevatt
Jianjing
J
Cao
Michelle
M
Taylor
Christina Z
CZ
Floresca
Ji-Kyung
JK
Choi
Bruce G
BG
Jenkins
Robert R
RR
Luedtke
Amy Hauck
AH
Newman
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008024:Ligands; D008279:Magnetic Resonance Imaging; D008938:Mitosis / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics; D011869:Radioligand Assay; D051381:Rats; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019966:Substance-Related Disorders / Q000188:drug therapy*
D000577:Amides; D001549:Benzamides; D008024:Ligands; C497150:N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyl)-4-pyridine-2-ylbenzamide; D010879:Piperazines; D011725:Pyridines; D050637:Receptors, Dopamine D3