Effects of two novel D3-selective compounds, NGB 2904 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide] and CJB 090 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide], on the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys
Effects of two novel D3-selective compounds, NGB 2904 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide] and CJB 090 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide], on the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys
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DOI：
10.1124/jpet.106.113571
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发表时间：
2007-05-01
影响因子：
3.5
通讯作者：
Nader, Michael A.
中科院分区：
文献类型：
--
作者：
Martelle, Jennifer L.;Claytor, Renee;Nader, Michael A.
本研究检测了两种新型多巴胺D3受体化合物NGB 2904 [ N-（4-（4-（2，3-二氯苯基）哌嗪-1-基）丁基）-9H-芴-2-甲酰胺]，一种拮抗剂，和CJB 090 [ N-（4-（4-（2，3-二氯苯基）哌嗪-1-基）丁基）-4-（吡啶-2-基）苯甲酰胺]，一种部分激动剂，在恒河猴的两种可卡因滥用模型中。为了确定剂量范围和作用的时间过程，当i. M. 15、30或120分钟。接下来，恒河猴被训练来辨别i。M.注射盐水（0.5ml）和可卡因（0.3mg/ kg）。在任何猴中，D-3化合物（0.03 - 3.0 mg/ kg; n = 3）均未替代可卡因。当与可卡因联合给药时，CJB 090而不是NGB 2904减弱了可卡因的辨别刺激作用，使可卡因剂量-反应曲线向右移动。在另一组猴中，在食物（1.0 g颗粒; n = 3）或可卡因（0.1 mg/ kg/注射; n = 4）给药的二级方案下维持反应。当反应稳定时，NGB 2904（1.0 - 5.6mg/ kg i. v.）的或CJB 090（0.3 - 3.0mg/ kg i. v.）的在会议之前立即连续施用5天。CJB 090，而不是NGB 2904，减少可卡因和食物维持反应。这些数据表明，对D3受体具有相对高的亲和力和选择性的化合物可以减弱可卡因的辨别和增强刺激作用，而不产生可卡因样作用。目前的研究结果支持继续检查的D 3化合物作为药理学工具，更好地了解这种受体亚型在可卡因成瘾的作用，并作为潜在的先导化合物的新型治疗药物。
The present study examined the effects of two novel dopamine D 3 receptor compounds, NGB 2904 [ N-( 4-( 4-( 2,3- dichlorophenyl) piperazin- 1- yl) butyl)- 9H- fluorene- 2- carboxamide], an antagonist, and CJB 090 [ N-( 4-( 4-( 2,3- dichlorophenyl) piperazin-1- yl) butyl)- 4-( pyridin- 2- yl) benzamide], a partial agonist, in two models of cocaine abuse in rhesus monkeys. To establish a dose range and time course of effects, both compounds were shown to block quinpirole- induced yawning when administered i. m. 15, 30, or 120 min before quinpirole. Next, rhesus monkeys were trained to discriminate i. m. injections of saline ( 0.5 ml) and cocaine ( 0.3 mg/ kg). Neither D-3 compound ( 0.03 - 3.0 mg/ kg; n = 3) substituted for cocaine in any monkey. When given in combination with cocaine, CJB 090 but not NGB 2904 attenuated the discriminative stimulus effects of cocaine, shifting the cocaine dose-response curve to the right. In a separate group monkeys, responding was maintained under a second- order schedule of either food ( 1.0- g pellets; n = 3) or cocaine ( 0.1 mg/ kg/ injection; n = 4) presentation. When responding was stable, a dose of NGB 2904 ( 1.0 - 5.6 mg/ kg i. v.) or CJB 090 ( 0.3 - 3.0 mg/ kg i. v.) was administered for 5 consecutive days, immediately before the session. CJB 090, but not NGB 2904, decreased cocaine- and food- maintained responding. These data indicate that compounds with relatively high affinity and selectivity for the D 3 receptor can attenuate the discriminative and reinforcing stimulus effects of cocaine while not producing cocaine- like effects. The present findings support the continued examination of D 3 compounds as pharmacological tools for better understanding the role of this receptor subtype in cocaine addiction and as potential lead compounds for novel therapeutic agents.