Synthesis and biologic activity of conformationally constrained analogs of L-363,301.
We report the synthesis, biological activity and conformational analysis of analogs of the cyclic hexapeptide L-363,301, c[Pro6-Phe7-D-Trp8-Lys9-Thr10-Phe11] (numbering as in the native hormone somatostatin-14). The d-Trp in position 8 was replaced with (2R,3S)- and (2R,3R)-beta-MeTrp respectively, with an added methyl group in the beta position of Trp. The objective of our study was to determine the potency and selectivity generated by the added constraint in the beta position of the d-Trp upon binding to human somatostatin receptors hsst1-5. We synthesized the building blocks enantioselectively and incorporated them into the peptides by SPPS. Competition binding assays revealed that both compounds 2 and 3 were selective for hsst2 over hsst5. The (2R,3S) analog 2 was approximately 30 times more potent at hsst2 than the (2R,3R) analog 3. Interestingly, the (2R,3R) compound showed no binding affinity at hsst5.
Moore
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SB
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0343, USA. jpt@chem.ucsd.edu
Grant
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M
Rew
Y
Y
Bosa
E
E
Fabbri
M
M
Kumar
U
U
Goodman
M
M
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry; D003198:Computer Simulation; D003500:Cyclization; D008958:Models, Molecular; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000378:metabolism*; D011487:Protein Conformation; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D000596:Amino Acids; D010446:Peptide Fragments; D010455:Peptides; D010456:Peptides, Cyclic; C040704:cyclo(Pro-Phe-Trp-Lys-Thr-Phe); D013004:Somatostatin