GSK962040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility
GSK962040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility
复制标题
DOI：
10.1111/j.1365-2982.2009.01270.x
复制
发表时间：
2009-06
影响因子：
3.5
通讯作者：
Gareth J. Sanger;S. Westaway;A. A. Barnes-A.;David T. MacPherson;Alison I. Muir;E. Jarvie;V. N. Bolton;Selim Cellek;Erik Näslund;Per M. Hellström;Richard A. Borman;W. P. Unsworth;Kim L. Matthews;Kevin Lee
中科院分区：
文献类型：
--
作者：
Gareth J. Sanger;S. Westaway;A. A. Barnes-A.;David T. MacPherson;Alison I. Muir;E. Jarvie;V. N. Bolton;Selim Cellek;Erik Näslund;Per M. Hellström;Richard A. Borman;W. P. Unsworth;Kim L. Matthews;Kevin Lee
摘要临床上迫切需要一种安全、有效的胃排空刺激剂;目前的治疗方法包括红霉素（一种具有额外特性的抗生素，可排除长期使用）和甲氧氯普胺（一种5-羟色胺4型受体激动剂和脑D2受体拮抗剂，与运动障碍相关）。为了摆脱红霉素复杂的胃动素结构，鉴定并表征了小分子胃动素受体激动剂GSK 962040。使用重组人受体、已知对胃动素有反应的兔和人离体胃制备物，通过测量其增加清醒兔排便的能力，在体内评价该化合物。在人胃动素受体上，GSK 962040和红霉素作为激动剂的pEC 50（EC 50值以10为底的负对数，产生50%最大反应的激动剂浓度）值分别为7.9和7.3; GSK 962040对一系列其他受体（包括胃饥饿素）、离子通道和酶无显著活性。在兔胃窦中，GSK 962040 300 nmol L−1-10 μmol L−1导致胆碱能介导的收缩幅度延长，在3 μmol L−1时达到最大值248 ± 47%。在人离体胃中，GSK 962040 10 μmol L−1、红霉素10 μmol L−1和[Nle 13]-胃动素100 nmol L−1均引起幅度相似的肌肉收缩。在清醒家兔中，静脉注射5 mg kg−1 GSK 962040或10 mg kg−1红霉素可显著增加2 h内的粪便排出量。总之，这些数据表明，GSK 962040，一种非胃动素结构，选择性激活胃动素受体。简化激活这种受体的结构要求，极大地促进了潜在的胃轻瘫新药的设计。
Abstract There is an urgent clinical need for a safe, efficacious stimulant of gastric emptying; current therapies include erythromycin (an antibiotic with additional properties which preclude chronic use) and metoclopramide (a 5‐hydroxytryptamine type 4 receptor agonist and an antagonist at brain D2 receptors, associated with movement disorders). To move away from the complex motilide structure of erythromycin, a small molecule motilin receptor agonist, GSK962040, was identified and characterized. The compound was evaluated using recombinant human receptors, rabbit and human isolated stomach preparations known to respond to motilin and in vivo, by measuring its ability to increase defecation in conscious rabbits. At the human motilin receptor, the pEC50 (the negative logarithm to base 10 of the EC50 value, the concentration of agonist that produces 50% of the maximal response) values for GSK962040 and erythromycin as agonists were, respectively, 7.9 and 7.3; GSK962040 had no significant activity at a range of other receptors (including ghrelin), ion channels and enzymes. In rabbit gastric antrum, GSK962040 300 nmol L−1–10 μmol L−1 caused a prolonged facilitation of the amplitude of cholinergically mediated contractions, to a maximum of 248 ± 47% at 3 μmol L−1. In human‐isolated stomach, GSK962040 10 μmol L−1, erythromycin 10 μmol L−1 and [Nle13]‐motilin 100 nmol L−1, each caused muscle contraction of similar amplitude. In conscious rabbits, intravenous doses of 5 mg kg−1 GSK962040 or 10 mg kg−1 erythromycin significantly increased faecal output over a 2‐h period. Together, these data show that GSK962040, a non‐motilide structure, selectively activates the motilin receptor. Simplification of the structural requirements to activate this receptor greatly facilitates the design of potentially new medicines for gastroparesis.