Highly potent 4-amino-indolo[2,3-c]azepin-3-one-containing somatostatin mimetics with a range of sst receptor selectivities.
The synthesis, biological evaluation, and conformational analysis of 4-amino-indolo[2,3-c]azepin-3-one (Aia)-containing SRIF mimetics are reported. Different subtype selectivities are observed depending on the N- and C-terminal substituents of the D-Aia-Lys dipeptide mimetic. An sst(5)-selective analogue with subnanomolar binding affinity was obtained that is the most potent agonist reported to date. A nonselective mimetic with high potency was also identified. This study allows a better definition of the bioactive conformation of the essential D-Trp side chain in the somatostatin pharmacophore.
Feytens
Debby
D
Department of Organic Chemistry, Vrije Universiteit Brussel, Brussels, Belgium.
De Vlaeminck
Magali
M
Cescato
Renzo
R
Tourwé
Dirk
D
Reubi
Jean Claude
JC
D000588:Amines / Q000737:chemistry*; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000378:metabolism*; D013004:Somatostatin / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000588:Amines; D001381:Azepines; D007211:Indoles; D010455:Peptides; D017481:Receptors, Somatostatin; D013004:Somatostatin