title: Effect of dexloxiglumide and spiroglumide, two new CCK-receptor antagonists, on gastric emptying and secretion in the rat: evaluation of their receptor selectivity in vivo.
abstract: BACKGROUND
  Clear definition of the role of CCK in the physiology of gastric motor activity has been long hampered by the lack of specific and potent nonpeptide antagonists of CCK-receptors. The availability of such compounds has stimulated a broad array of investigations into the physiological actions of this hormone and to examine its putative role in certain diseases.
  
  
  OBJECTIVE
  The effect of two recently developed CCK-receptor antagonists, namely dexloxiglumide and spiroglumide, on gastric emptying and secretion as well as their selectivity towards CCKA- and CCKB-receptors in vivo was studied in the rat.
  
  
  METHODS
  Gastric emptying was quantified by using a liquid noncaloric meal labelled with phenol red. Acid secretion was measured by titration in conscious rats.
  
  
  RESULTS
  The putative CCKA-antagonist, dexloxiglumide, administered by intravenous route, was able to inhibit CCK-8-induced delay of gastric emptying in a dose-dependent fashion, with an ID50 (95% CL) of 1.14 (0.84-1.53) mg/kg. Similarly, the putative CCKB-gastrin-antagonist, spiroglumide, proved to be capable of inhibiting dose-dependently pentagastrin-induced acid hypersecretion, its ID50 being 20.1 (8.67-46.4) mg/kg. On the other hand, dexloxiglumide, at doses able to almost completely block CCKA mediated effects (i.e. delay of gastric emptying), was ineffective against pentagastrin-induced acid hypersecretion. Similarly, spiroglumide, at doses which inhibit by 55% CCKB-gastrin mediated effects (i.e. acid secretion) was inactive when tested against CCK-8 induced delay of gastric emptying.
  
  
  CONCLUSIONS
  These results demonstrate in vivo that dexloxiglumide is a selective antagonist for CCKA-receptors whereas spiroglumide is selective for CCKB-gastrin-receptors. These compounds are therefore useful tools for discriminating between different subclasses of CCK-receptors in vivo and might have a therapeutic potential in motility or acid-related disorders.
authors.affiliation: Institute of Pharmacology, School of Medicine and Dentistry, University of Parma, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Scarpignato
authors.forename: I
authors.initials: I
authors.lastname: Kisfalvi
authors.forename: M
authors.initials: M
authors.lastname: D'Amato
authors.forename: G
authors.initials: G
authors.lastname: Varga
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism*; D005746:Gastric Emptying / Q000187:drug effects*; D006727:Hormone Antagonists / Q000494:pharmacology*; D007651:Keto Acids / Q000494:pharmacology*; D008297:Male; D010418:Pentagastrin / Q000494:pharmacology; D010421:Pentanoic Acids / Q000494:pharmacology*; D011377:Proglumide / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000819:agonists / Q000037:antagonists & inhibitors*; D012844:Sincalide / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology*
chemical_list: D006727:Hormone Antagonists; D007651:Keto Acids; D010421:Pentanoic Acids; D011949:Receptors, Cholecystokinin; D013141:Spiro Compounds; C103490:dexloxiglumide; C053737:loxiglumide; D010418:Pentagastrin; D011377:Proglumide; C076954:spiroglumide; D012844:Sincalide