Differences between the abilities of tegaserod and motilin receptor agonists to stimulate gastric motility in vitro.
OBJECTIVE
Motilin or 5-HT4 receptor agonists stimulate gastrointestinal motility. Differences in activity are suggested but direct comparisons are few. A method was devised to directly compare the gastric prokinetic activities of motilin, the motilin receptor agonist, erythromycin, and the 5-HT4 receptor agonist, tegaserod.


METHODS
Gastric prokinetic-like activity was assessed by measuring the ability to facilitate cholinergically-mediated contractions evoked by electrical field stimulation (EFS) in rabbit isolated stomach. Comparisons were made between potency, maximal activity and duration of responses.


RESULTS
Rabbit motilin (r.motilin) 0.003-0.3 microM, [Nle13]motilin 0.003-0.3 microM, erythromycin 0.3-10 microM and tegaserod 0.1-10 microM caused concentration - dependent potentiation of EFS-evoked contractions. The potency ranking was r.motilin = [Nle13]motilin > tegaserod > erythromycin. The Emax ranking was r.motilin = [Nle13]motilin = erythromycin > tegaserod. Responses to r.motilin and [Nle13]motilin faded rapidly (t1/2 9 and 11 min, respectively) whereas those to erythromycin and tegaserod were maintained longer (t1/2 24 and 28 min). The difference did not appear to be due to peptide degradation. A second application of [Nle13]motilin was excitatory after 60 min contact and fade of the initial response (responses to 0.03 and 0.1 microM [Nle13]motilin were not different from those caused by the first application).


CONCLUSIONS
Prokinetic-like activities of the 5-HT4 agonist tegaserod and the motilin receptor agonists were compared by measuring changes in cholinergically-mediated contractions. This novel approach highlighted important differences between classes (greater Emax of motilin, compared with tegaserod) and for the first time, within each class (short t1/2 for motilin, compared with erythromycin).
Jarvie
E M
EM
Neurology & Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Limited, New Frontiers Science Park, Harlow, Essex UK.
North Laidler
V J
VJ
Corcoran
S
S
Bassil
A
A
Sanger
G J
GJ
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004917:Erythromycin / Q000494:pharmacology; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006207:Half-Life; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D008365:Manometry; D009037:Motilin / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D011817:Rabbits; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists*; D018013:Receptors, Neuropeptide / Q000819:agonists*; D044422:Receptors, Serotonin, 5-HT4 / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013268:Stimulation, Chemical
D005765:Gastrointestinal Agents; D007211:Indoles; D008024:Ligands; D018721:Muscarinic Agonists; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; D017366:Serotonin Receptor Agonists; C050802:motilin receptor; D044422:Receptors, Serotonin, 5-HT4; C105050:tegaserod; D009037:Motilin; D004917:Erythromycin; D002217:Carbachol