title: N alpha-carboxyacyl analogues of CCK with a substituted Gly: interaction with pancreatic and gallbladder CCK receptors.
abstract: It has been reported that certain N alpha-carboxyacyl analogues of CCK-8 and of CCK-7 with a substituted Gly in position 3 or 4 of the peptide possess higher potencies at stimulating pancreatic enzyme secretion than at stimulating gallbladder contraction, suggesting that these analogues are able to differentiate subtypes of CCKA receptors. However, no studies examined directly the interaction of these peptides with the CCK receptors in both tissues. In the present study, CCK-8 and various N alpha-carboxyacyl analogues of CCK-7 and of CCK-8 were prepared by solid phase synthesis using Fmoc chemistry and were purified by HPLC; molecular weight and sufficient sulfation were determined by mass spectrometry. [125I]Bolton-Hunter(BH)-CCK-8 binding to sections of the guinea pig pancreas and gallbladder was determined under identical conditions; amylase release from pancreatic acini and contraction of gallbladder muscle strips were measured in vitro. Each peptide stimulated amylase release (EC50): CCK-8 (0.09 nM) > Suc[Sar3]CCK-7 (0.23 nM) > des(SO3)CCK-8 (28 nM) > Suc[D-Trp4]CCK-8 (32 nM) > Suc[D-Trp3]CCK-7 (53 nM) > Pht[D-Trp3]CCK-7 (180 nM) > Glt[D-Trp3]CCK-7 (220 nM). The same relative potencies were found for stimulation of gallbladder contraction, and for the inhibition of [125I]BH-CCK-8 binding to pancreas and gallbladder sections. These data demonstrate that the CCKA receptors in the pancreas and on gallbladder smooth muscle possess similar affinities for the various N alpha-carboxyacyl analogues of CCK-7 and CCK-8 with a substituted Gly and provide further evidence that the CCKA receptors in gallbladder and pancreas cannot be distinguished pharmacologically.
authors.affiliation: Department of Medicine, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: von Schrenck
authors.forename: K
authors.initials: K
authors.lastname: Müller
authors.forename: C
authors.initials: C
authors.lastname: Schulze
authors.forename: S
authors.initials: S
authors.lastname: Mirau
authors.forename: A
authors.initials: A
authors.lastname: Raedler
authors.forename: H
authors.initials: H
authors.lastname: Greten
mesh_terms: D000681:Amylases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002766:Cholecystokinin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D005704:Gallbladder / Q000187:drug effects* / Q000378:metabolism; D005998:Glycine; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D011949:Receptors, Cholecystokinin / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D011949:Receptors, Cholecystokinin; D002766:Cholecystokinin; D000681:Amylases; D005998:Glycine