LOPERAMIDE BINDING TO OPIATE RECEPTOR-SITES OF BRAIN AND MYENTERIC PLEXUS

Abstract

Loperamide, a new antidiarrheal agent, was tested to determine whether its biological activity involves binding to opiate receptor sites. Loperamide and morphine competitively inhibited 3H-naloxone binding to homogenates of guinea-pig brain and myenteric plexus. The Kd values obtained in the presence of Na were: morphine, 9.60.cntdot.10-9 M (brain), 1.66.cntdot.10-7 M (myenteric plexus); loperamide, 7.20.cntdot.10-9 M (brain), 1.33.cntdot.10-7 M (myenteric plexus); naloxone, 4.78.cntdot.10-10 M (brain), 1.27.cntdot.10-9 M (myenteric plexus). In the absence of Na, binding of loperamide and morphine to brain homogenate was enhanced while the binding of naloxone was reduced. Morphine (IC50 [concentration producing 50% inhibition] = 7.5.cntdot.10-8 M) and loperamide (IC50 = 6.9.cntdot.10-9 M) inhibited the electrically induced contractions of longitudinal muscle from guinea-pig ileum, and naloxone competitively antagonized these effects. The Kd value calculated for the interaction of naloxone with binding sites associated with the contracting muscle was between 0.98.cntdot.10-9 M and 1.85.cntdot.10-9 M. In the mouse hot plate test, s.c. administration of morphine (minimal effective dose = 6.6 .mu.mol/kg) and loperamide (minimal effective dose = 78 .mu.mol/kg) delayed the response to heat stimuli and this effect was completely blocked by prior administration of naloxone. In the anesthetized dog, i.v. administration of morphine (100 .mu.g/kg) and loperamide (100 .mu.g/kg) enhanced the contractile activity of circular muscle in proximal and distal duodenum, distal ileum and proximal colon but duodenal longitudinal muscle was relaxed; these effects were completely reversed by subsequent administration of naloxone. Loperamide binds to opiate receptor sites and possesses opiate agonist activity both in vivo and in vitro.