In vitro Pharmacological Characterization of Mitemcinal (GM-611), the First Acid-Resistant Non-Peptide Motilin Receptor Agonist, in Smooth Muscle of Rabbit Small Intestine

Abstract

The pharmacological properties of mitemcinal (GM-611), the first acid-resistant non-peptide motilin agonist, were investigated in the smooth muscle of the rabbit small intestine and compared with porcine motilin (pMTL), erythromycin A (EMA) and its derivatives (EM-523, EM-574 and ABT-229). Mitemcinal, pMTL, EMA, EM-523, EM-574 and ABT-229 produced concentration-dependent contractions with approximately the same maximum contractions in the isolated rabbit duodenum longitudinal strips. The contractile response to mitemcinal or pMTL was competitively inhibited by a selective motilin antagonist, GM-109. The pA₂ values for GM-109 as an antagonist of mitemcinal and pMTL showed approximately the same values. However, the concentration-dependent contractile responses to mitemcinal or pMTL were not affected by pretreatment with atropine, tetrodotoxin, hexamethonium, naloxone or tropisetron. The removal of calcium ions from the medium and pretreatment with verapamil greatly suppressed the contractions induced by mitemcinal and pMTL. The contractile response to mitemcinal was not affected by preincubation in acidic solutions, while those of EM-523, EM-574 and ABT-229 were strongly diminished in the same condition. Mitemcinal as well as other motilin agonists displaced ¹²⁵I-pMTL bound to a homogenate of the rabbit duodenum muscle tissue. The displacement curves of all these compounds were parallel. These results indicate that mitemcinal is a selective and full motilin receptor agonist in the smooth muscle of the rabbit small intestine and that this agent has an excellent acid-resistant property.

Guide to Receptors and Channels (GRAC), 5th edition

“…Principal transduction Gq/11 (Depoortere and Peeters, 1995;Feighner et al, 1999) Rank order of potency Motilin > ABT229, mitemcimal >erythromycin (Clark et al, 1999) = GSK962040 (Sanger et al, 2009) Selective agonists ABT229 (Lartey et al, 1995), mitemcinal (Koga et al, 1994;Takanashi et al, 2007), GSK962040 (Sanger et al, 2009) Selective antagonists MA2029 (pA2 9.2, Sudo et al, 2008), GM109 (Takanashi et al, 1995;pA2 7.2-7.5 Clark et al, 1999) Probes Feighner et al, 1999) In rodents, the gene encoding the motilin precursor appears to be absent, while the receptor appears to be a pseudogene. Functions of motilin are not usually detected in rodents, although brain and other responses to motilin have been reported; the mechanism of action is obscure (see Sanger et al, 2011).…”

Effects of Mitemcinal (GM-611), an Acid-Resistant Nonpeptide Motilin Receptor Agonist, on the Gastrointestinal Contractile Activity in Conscious Dogs

“…ic conditions, such as those found in the stomach [9,10] , preclinical in vivo studies of these EMA derivatives have usually been performed by intravenous or intraduodenal administration [11][12][13] . Demonstrating the efficacy of EMA derivatives after oral administration was considered likely to be difficult because they degrade under acidic conditions.…”

7tm Receptors

“…Other names MTLR1 (Feighner et al, 1999), GPR38 (Mckee et al, 1997) Ensembl ID ENSG00000102539 Principal transduction Gq/11 (Depoortere and Peeters, 1995);Feighner et al, 1999) Rank order of potency Motilin > ABT229, mitemcimal > erythromycin (Clark et al, 1999) Selective agonists ABT229 (Lartey et al, 1995), mitemcinal (Koga et al, 1994;Takanashi et al, 2007) Selective antagonists GM109 (Takanashi et al, 1995); pA2 7.2-7. 5 Clark et al, 1999 …”