DESIGN AND SYNTHESIS OF DRUGS ACTING ON CENTRAL AND PERIPHERAL TISSUES

作用于中枢和外周组织的药物的设计与合成

• 批准号: 3840503
• 负责人: K C RICE
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3840503
• 关键词: central nervous system; cocaine; dopamine; dopamine receptor; drug addiction antagonist; drug design /synthesis /production; drug metabolism; endorphins; immune system; immunoregulation; laboratory rat; morphine; narcotic antagonists; neuroendocrine system; neuropharmacology; neurotransmitters; opioid receptor; piperazines; positron emission tomography; receptor binding; single photon emission computed tomography

Synthetic programs are continuing to develop new ligands for imaging brain drug receptors by positron emission tomography (PET) and single photon emission computed tomography (SPECT) scanning, and the NIH Opiate Total Synthesis is employed to provide previously inaccessible unnatural enantiomers of opiates and derivatives. The binding characteristics, pharmacology, immunochemistry, and the multiplicity of opioid receptors were examined, and new drugs were explored as treatment agents for cocaine abuse and for their interaction with the dopamine transporter. Multiple delta opioid receptors - Ligand binding data, utilized to determine whether subtypes of the delta opioid receptor existed in rat brain membranes, supported pharmacological studies demonstrating delta receptor subtypes which mediate antinociception. Immunoregulatory opioids - Opioid compounds, such as morphine and beta- endorphin, are active immunoregulatory molecules in vitro and in vivo, and opioid receptors are present on immune cells. We found that the lymphocyte mu-class binding site has a molecular eight of 58 kDa under nonreducing conditions and 70 kDa under reducing conditions, compared with brain mu- class binding sites which were found to have a molecular weight of 54 kDa under nonreducing conditions. These and other data indicate the presence of a functional m-type opioid receptor on cells of the immune system and add to the concept of bidirectional circuitry between the immune and neuroendocrine systems. Potential treatment agents for cocaine abuse - The high affinity dopamine reuptake inhibitor 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3- phenylpropyl]piperazine (GBR 12909) produced a dose-dependent decrease in the binding of [3H] cocaine or [3H]GBR 12935 to the dopamine transporter. GBR 12909 antagonizes the ability of cocaine to elevate extracellular dopamine by 50%. Further studies will be needed to evaluate a possible role for GBR 12909 in the medical treatment of cocaine addiction.

合成程序正在继续开发用于脑成像的新配体 通过正电子发射断层扫描 (PET) 和单光子检测药物受体 发射计算机断层扫描 (SPECT) 扫描和 NIH 阿片类药物总量 采用合成来提供以前无法获得的非自然 阿片类药物及其衍生物的对映体。 结合特性， 药理学、免疫化学和阿片受体的多样性 进行了检查，并探索了新药物作为可卡因的治疗剂 滥用及其与多巴胺转运蛋白的相互作用。 多个 delta 阿片受体 - 配体结合数据，用于 确定大鼠体内是否存在δ阿片受体亚型 脑膜，支持药理学研究证明 delta 介导抗伤害作用的受体亚型。 免疫调节阿片类药物 - 阿片类化合物，例如吗啡和 β- 内啡肽是体外和体内的活性免疫调节分子， 阿片受体存在于免疫细胞上。 我们发现淋巴细胞 mu-类结合位点在非还原条件下具有 58 kDa 的分子八 条件下和还原条件下 70 kDa 相比，脑 mu- 发现分子量为 54 kDa 的类结合位点 在非还原条件下。 这些和其他数据表明存在 免疫系统细胞上功能性 m 型阿片受体的作用 添加免疫和免疫之间双向电路的概念 神经内分泌系统。 可卡因滥用的潜在治疗药物 - 高亲和力多巴胺 再摄取抑制剂 1-[2-[双(4-氟苯基)甲氧基]乙基]-4-[3- 苯丙基]哌嗪 (GBR 12909) 产生剂量依赖性的降低 [3H]可卡因或[3H]GBR 12935与多巴胺转运蛋白的结合。 GBR 12909 拮抗可卡因升高细胞外细胞的能力 多巴胺减少 50%。 需要进一步的研究来评估可能的 GBR 12909 在可卡因成瘾的医学治疗中的作用。