CCK(2) receptor antagonists containing the conformationally constrained phenylalanine derivatives, including the new amino acid Xic.
The conformationally constrained analogues of phenylalanine, tetrahydroisoquinoline-3-carboxylic acid (Tic), Sic, Hic and Nic, and the new amino acid Xic have been incorporated into a potent and highly selective cholecystokinin-2 (CCK(2)) receptor antagonist (2) in place of the phenylalanine residue, producing compounds 15a-e. High selectivities for CCK(2) over CCK(1) were observed for compounds 15a-e. The in vitro profile of the analogue containing the Nic residue (15d) was identical to that of compound 2, whereas the alternative conformational constraints resulted in a significant loss of affinity. The apparent advantage of Nic in the context of these CCK(2) ligands was subsequently demonstrated to be statistically significant.
Gibson
Susan E
SE
Department of Chemistry, King's College London, Strand, UK.
Guillo
Nathalie
N
Jones
Jerome O
JO
Buck
Ildiko M
IM
Kalindjian
S Barret
SB
Roberts
Sonia
S
Tozer
Matthew J
MJ
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D006168:Guinea Pigs; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000737:chemistry; D008024:Ligands; D051379:Mice; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry*; D051381:Rats; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013270:Stomach / Q000187:drug effects; D044005:Tetrahydroisoquinolines
D006574:Heterocyclic Compounds, 2-Ring; D007546:Isoquinolines; D008024:Ligands; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D044005:Tetrahydroisoquinolines; C031270:1,2,3,4-tetrahydroisoquinoline carboxylic acid; D010649:Phenylalanine