title: Ring size in octreotide amide modulates differently agonist versus antagonist binding affinity and selectivity.
abstract: H-DPhe (2)-c[Cys (3)-Phe (7)-DTrp (8)-Lys (9)-Thr (10)-Cys (14)]-Thr (15)-NH2 (1) (a somatostatin agonist, SRIF numbering) and H-Cpa (2)-c[DCys (3)-Tyr (7)-DTrp (8)-Lys (9)-Thr (10)-Cys (14)]-Nal (15)-NH2 (4) (a somatostatin antagonist) are based on the structure of octreotide that binds to three somatostatin receptor subtypes (sst 2/3/5) with significant binding affinity. Analogues of 1 and 4 were synthesized with norcysteine (Ncy), homocysteine (Hcy), or D-homocysteine (DHcy) at positions 3 and/or 14. Introducing Ncy at positions 3 and 14 constrained the backbone flexibility, resulting in loss of binding affinity at all sst s. The introduction of Hcy at positions 3 and 14 improved selectivity for sst 2 as a result of significant loss of binding affinity at the other sst s. Substitution by DHcy at position 3 in the antagonist scaffold (5), on the other hand, resulted in a significant loss of binding affinity at sst 2 and sst 3 as compared to the different affinities of the parent compound (4). The 3D NMR structures of the analogues in dimethylsulfoxide are consistent with the observed binding affinities.
authors.affiliation: Structural Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Christy Rani R
authors.initials: CR
authors.lastname: Grace
authors.forename: Judit
authors.initials: J
authors.lastname: Erchegyi
authors.forename: Manoj
authors.initials: M
authors.lastname: Samant
authors.forename: Renzo
authors.initials: R
authors.lastname: Cescato
authors.forename: Veronique
authors.initials: V
authors.lastname: Piccand
authors.forename: Roland
authors.initials: R
authors.lastname: Riek
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Jean E
authors.initials: JE
authors.lastname: Rivier
mesh_terms: D002460:Cell Line; D003545:Cysteine / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D015282:Octreotide / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D017481:Receptors, Somatostatin; D003545:Cysteine; D015282:Octreotide