Stable Expression of a Synthetic Gene for the Human Motilin Receptor: Use in an Aequorin-Based Receptor Activation Assay

Structure−Activity Relationships of 9-Substituted-9-Dihydroerythromycin-Based Motilin Agonists: Optimizing for Potency and Safety

“…1,2 The activity of motilin is mediated through a G-protein coupled receptor found on smooth muscle and enteric neurons in the GI tract. [3][4][5][6] The macrolide erythromycin A (EryA) 1 is an agonist of the motilin receptor (EC 50 ∼1 uM) (Figure 1); 1,7 it competes with labeled motilin for receptor sites in membrane preparations, 8 causes Ca 2þ currents in whole cell systems expressing the receptor, 9,10 induces contractions in isolated GI smooth muscle, 8,11 and is an effective prokinetic in animal models which measure gastric emptying 12 and motility. 7,13 Indeed, both motilin and 1 stimulate gastric motility in patients with gastroparesis, 14,15 and clinical studies indicate that 1 has a stronger effect on gastric emptying than metoclopramide, domperidone, or cisapride and is capable of providing symptomatic relief to gastroparesis patients.…”

“…The 22-amino acid hormone motilin plays a critical role in the normal regulation of gastrointestinal (GI a Abbreviations: GI, gastrointestinal; EryA, erythromycin A; hERG, human ether-a-go-go related gene; GERD, gastresophageal reflux disease; TMSE, trimethylsilylethyl; TBAF, tetrabutylammonium fluoride; TBDMS, tert -butyldimethylsilyl; EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; ELSD, evaporative light scattering detector; MIC, minimal growth inhibitory concentration. ) motility. , The activity of motilin is mediated through a G-protein coupled receptor found on smooth muscle and enteric neurons in the GI tract. − The macrolide erythromycin A (EryA) 1 is an agonist of the motilin receptor (EC 50 ∼1 uM) (Figure ); , it competes with labeled motilin for receptor sites in membrane preparations, causes Ca 2+ currents in whole cell systems expressing the receptor, , induces contractions in isolated GI smooth muscle, , and is an effective prokinetic in animal models which measure gastric emptying and motility. , Indeed, both motilin and 1 stimulate gastric motility in patients with gastroparesis, , and clinical studies indicate that 1 has a stronger effect on gastric emptying than metoclopramide, domperidone, or cisapride and is capable of providing symptomatic relief to gastroparesis patients. , Nevertheless, the antibiotic activity of 1 is undesirable in a prokinetic agent that could require chronic use. Nonantibiotic erythromycin derived motilin agonists (often referred to as “motilides”) have therefore been proposed for the treatment of GI motility disorders such as gastresophageal reflux disease (GERD) and gastroparesis …”

GPCR Drug Discovery Through the Exploitation of Allosteric Drug Binding Sites

“…Receptors that do not naturally regulate intracellular calcium can be redirected to regulate this secondary messenger by coexpression with either a promiscuous G-protein, such as Gα 15/16 (Offermanns and Simon 1995), or with a chimeric G-protein, such as Gα q/i5 or Gα q/s5 in which the N-terminal five amino acids of Gα q have been replaced with the corresponding amino acids of Gα i or Gα s (Milligan and Rees 1999). The detection of intracellular calcium can also be detected following coexpression of the calcium-sensitive photoprotein aequorin (Carreras et al 2002).…”

9-Dihydroerythromycin ethers as motilin agonists—Developing structure–activity relationships for potency and safety

“…[3][4][5][6] Erythromycin A 1, a 14-membered macrolide antibiotic, also acts as an agonist of the motilin receptor (EC 50 $1 lM). 1,7 Indeed it has been shown to compete with labeled motilin for receptor sites in membrane preparations, 8 causes Ca 2+ currents in whole cell systems expressing the receptor, 9,10 induces contractions in isolated GI smooth muscle 8,11 and is an effective prokinetic in animal models which measure gastric emptying 12 and motility. 13 Further, it has been proven clinically to stimulate gastric motility in patients with gastroparesis 14,15 and is able to provide symptomatic relief to patients with gastroparisis.…”