Hybrid peptides constructed from RES-701-1, an endothelin B receptor antagonist, and endothelin; Binding selectivity for endothelin receptors and their pharmacological activity

Hybrid peptides were constructed from endothelin B receptor (ETB) selective antagonist RES-701-1 (1) and endothelin (ET-1). They have N-terminal 10 am ino acids derived from 1 and C-terminal 10 amino acids derived from ET-1. R ES-701-1(1-10)-[Ala15]ET-1(12-21) and its analogues substituted or truncate d at the residues derived from RES-701-1 had proved to possess high recepto r binding activity selective for ETB as well as 1. Substitutions at the res idues derived from ET-1 had produced some analogues that possessed high aff inity not only for ETB but for ETA. Although all analogues had antagonistic effects on ETA, some analogues had proved to function as agonist on ETB co nfirmed by the changes in intracellular calcium concentrations of ET recept or-transfected COS-7 cells, We have found four types of ET receptor-binding peptides: (1) ETB-selective agonist with weak ETA antagonism (3, KT7421); (2) ETB-selective antagonist with weak ETA antagonism (29, KT7539); (3) ETB agonist with potent ETA antagonism (27, KT7538); and (4) non-selective ETA /ETB antagonist (26, KT7540). (C) 1998 Elsevier Science Ltd. All rights res erved.