SSTR1- and SSTR3-Selective Somatostatin Analogues

ROSARIO RAMÓN; PABLO MARTÍN-GAGO; XAVIER VERDAGUER; MARIA J. MACIAS; PAU MARTIN-MALPARTIDA; JIMENA FERNANDEZ-CARNEADO; MARC GOMEZ-CAMINALS; BERTA PONSATI; PILAR LÓPEZ-RUIZ; M. ALICIA CORTÉS; BEGOÑA COLÁS; ANTONI RIERA

CHEMBIOCHEM

WILEY-V C H VERLAG GMBH

Lugar: Weinheim; Año: 2011 vol. 12 p. 625 - 632

1439-4227

Factor de impacto (2011): 3,944 / Journal Ranking: Q1. We prepared the two enantiomers of 3-(3-quinolyl)-alanine(Qla, 1) in multigram scale by asymmetric hydrogenation.These amino acids, protected as Fmoc derivatives, were thenused in the solid-phase synthesis of two new somatostatin 14(SRIF-14) analogues 8a and 8b, tetradecapeptides in whichthe tryptophan residue (Trp8) is replaced by one of the twoenantiomers of 3-(3?-quinolyl)-alanine (Qla8) and therefore lackthe NH bond in residue 8. The selectivity of these new analoguesfor the somatostatin receptors, SSTR1-5, was measured.Substitution with l-Qla8 yielded peptide 8a, which was highlyselective for SSTR1 and SSTR3, with an affinity similar to that ofSRIF-14. Substitution by d-Qla gave the relatively selective analogue8b, which showed high affinity for SSTR3 and significantaffinity for SSTR1, SSTR2 and SSTR5. The biological results demonstratethat bulky and electronically poor aromatic aminoacids at position 8 are compatible with strong activity withSSTR1 and SSTR3. Remarkably, these high affinity levels wereachieved with peptides in which the conformational mobilitywas increased with respect to that of SRIF-14. This observationsuggests that conformational rigidity is not required, andmight be detrimental to the interaction with receptors SSTR1and SSTR3. The absence of an indole N proton in Qla8 mightalso contribute to the increased flexibility observed in theseanalogues.