Characterization of the transport, metabolism, and pharmacokinetics of the dopamine D3 receptor-selective fluorenyl- and 2-pyridylphenyl amides developed for treatment of psychostimulant abuse.
The recent discovery of novel high-affinity and selective dopamine D3 receptor (DA D3R) antagonists and partial agonists has provided tools with which to further elucidate the role DA D3R plays in substance abuse. The present study was conducted to evaluate the transport, metabolism, pharmacokinetics, and brain uptake of the DA D3R-selective fluorenyl amides, NGB 2904 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide] fumarate) and JJC 4-077 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-9H-fluorene-2-carboxamide hydrochloride], and the 2-pyridylphenyl amides, CJB 090 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridine-2-yl)benzamide hydrochloride] and PG 01037 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-trans-but-2-enyl)-4-(pyridine-2-yl)benzamide hydrochloride], all of which have been studied in animal models of psychostimulant abuse. Additional screening with a panel of human and rat Supersomes was performed for NGB 2904 and PG 01037. Drug-stimulated ATPase activation assays and bidirectional transport and efflux assays were used to test for substrate specificity of NGB 2904 and PG 01037 for human and rat efflux transporters. All compounds exhibited moderate elimination half-lives, ranging from 1.49 to 3.27 h, and large volumes of distribution (5.95-14.19 l/kg). The brain-to-plasma ratios ranged from 2.93 to 11.81 and were higher than those previously reported for cocaine. Brain exposure levels of NGB 2904 and PG 01037 were significantly reduced after intraperitoneal administration compared with intravenous administration. The metabolism of these compounds was mediated primarily by CYP3A subfamilies. PG 01037 was a P-glycoprotein-transported substrate. Higher doses of these compounds are often required for in vivo action, suggesting decreased bioavailability via extravascular administration that may be attributed to high drug efflux and hepatic metabolism. These studies provide important preclinical information for optimization of next-generation D3R selective agents for the treatment of drug addiction.
Mason
Clifford W
CW
Pharmacokinetics-Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, USA.
Hassan
Hazem E
HE
Kim
Kang-Pil
KP
Cao
Jianjing
J
Eddington
Natalie D
ND
Newman
Amy Hauck
AH
Voulalas
Pamela J
PJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D015259:Dopamine Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018492:Dopamine Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005449:Fluorenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D019966:Substance-Related Disorders / Q000188:drug therapy*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001549:Benzamides; D000697:Central Nervous System Stimulants; D065607:Cytochrome P-450 Enzyme Inhibitors; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D005449:Fluorenes; C545833:N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide; C116818:NGB 2904; D010879:Piperazines; D050637:Receptors, Dopamine D3; D000251:Adenosine Triphosphatases