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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >Behavioral effects and binding affinities of the fentanyl derivative OHM3507.
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Behavioral effects and binding affinities of the fentanyl derivative OHM3507.

机译：芬太尼衍生物OHM3507的行为效应和结合亲和力。

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摘要

Several fentanyl derivatives have been reported to have novel pharmacologies that might be exploited for developing alternate approaches to the treatment of pain. The purpose of the current series of studies was to evaluate OHM3507, a novel fentanyl derivative reported to have an unusual pharmacological profile in nonprimate species. Similar to several other fentanyl derivatives with clinical potential, OHM3507 had the highest affinity (IC50 = 10 nM) for mu ([3H]D-Ala2,N-Me-Phe4,Gly5-OH-labeled) receptors with 6- and 176-fold lower affinity for delta ([3H]D-Pen2-D-Pen5-labeled), and kappa ([3H]ethylketocyclazocine-labeled) receptors, respectively. In rhesus monkeys, OHM3507 shared discriminative stimulus effects with morphine, increased tail-withdrawal latencies in a warm-water procedure of antinociception, decreased ventilation in monkeys breathing normal air or 5% CO2, and failed to modify accuracy on acquisition and performance tasks up to doses that decreased rates of food-maintained responding. The opioid antagonists naltrexone and naltrindole antagonized the behavioral effects of OHM3507 in a manner that was consistent with mu-receptor mediation. Although OHM3507 appeared to have low efficacy opioid actions in nonprimate species, results from the current studies clearly show this compound to have strong, fentanyl-like mu agonist actions in rhesus monkeys. These results provide another example of the sometimes poor predictability in the behavioral pharmacology of fentanyl derivatives among species, in this case between monkeys and rats, mice and rabbits, and demonstrates the need for evaluating new drugs under a broad range of conditions to increase the probability of identifying novel compounds that can be used to treat pain.
机译：据报道，几种芬太尼衍生物具有新颖的药理作用，可用于开发替代疗法来治疗疼痛。本系列研究的目的是评估OHM3507，这是一种新型的芬太尼衍生物，据报道在非灵长类动物中具有非同寻常的药理作用。与具有临床潜力的其他几种芬太尼衍生物相似，OHM3507对mu（[3H] D-Ala2，N-Me-Phe4，Gly5-OH标记）的6和176-受体具有最高亲和力（IC50 = 10 nM）。分别对δ（[3H] D-Pen2-D-Pen5-标记）和κ（[3H]乙基酮基环偶氮星-标记）受体的亲和力低两倍。在恒河猴中，OHM3507与吗啡具有歧视性的刺激作用，在温水镇痛过程中尾缩潜伏期增加，呼吸正常空气或5％CO2的猴子的通气减少，并且未能改变采集和执行任务的准确性，直至降低食物维持反应率的剂量。阿片类药物纳曲酮和纳曲酮以与mu受体介导一致的方式拮抗OHM3507的行为作用。尽管OHM3507在非灵长类动物中似乎具有低效的阿片类药物作用，但目前的研究结果清楚地表明，该化合物在恒河猴中具有强大的芬太尼样mu激动剂作用。这些结果提供了另一个例子，即在物种之间，在猴子与大鼠，小鼠和兔子之间的物种中，芬太尼衍生物的行为药理学有时可预测性较差，并表明需要在广泛的条件下评估新药以增加可能性鉴定可用于治疗疼痛的新型化合物。

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