STRUCTURE-ACTIVITY-RELATIONSHIPS OF CYCLIC PENTAPEPTIDE ENDOTHELIN-A RECEPTOR ANTAGONISTS

Analogues of the natural product endothelin A (ET(A)) receptor antagon ists cyclo(-D-Trp(1)-D-Glu(2) Ala(3)-D-Val(4)-Leu(5)-) (1) and yclo(-D -Trp(1)-D-Glu(2)-Ala(3)-D-allone(4)-Leu(5)) (2) were prepared and test ed for inhibitory activity against [I-125]endothelin (ET-1) binding to protein ET(A) receptors. The DDLDL chirality sequence of the natural products appeared to be critical for inhibitory activity because conve rsion of either D-Trp or D-Glu (or both) in 1 to the corresponding L-i somer(s) abolished this property. Systematic modifications at each pos ition of the natural products clarified the structure-activity relatio nships and led to highly potent and selective ET(A) receptor antagonis ts. Most replacements of D-Trp(1) and Leu(5) with other amino acids ca used a significant loss of inhibitory activity. In contrast, replaceme nt of D-Glu(2) with D-Asp(2) enhanced the activity. With regard to the Ala(3) position, all analogues with imino acids, independent of being cyclic or acyclic, showed higher affinities than did the amino acid a nalogues. In addition, most replacements with amino acids, which had v arious functional groups in their side chains, did not significantly m odify ET(A) binding affinity. The D-Val(4)/D-alloIle(4) position was v ery important for inhibitory activity, and a beta-position branched D- amino acid or a D-heteroarylglycine was preferable at this position. A mong synthesized cyclic pentapeptides, compound 36 (BQ-518) was the mo st potent ETA receptor antagonist, with a pA(2) of 8.1 against ET-1-in duced vasoconstriction in isolated porcine coronary arteries. This com pound also showed the greatest selectivity between ET(A) and ET(B) rec eptors (IC50 for human ET(A) = 1.2 nM, IC50 for human ET(B) = 55 mu M) In contrast, compound 8 (BQ-123) is a highly soluble, potent, and sel ective ETA receptor antagonist (pA(2) = 7.4, IC50 for human ET(A) = 8. 3 nM, IC50 for human ET(B) = 61 mu M). The sodium salt of 8 is practic ally freely soluble in saline. These compounds are useful tools for no t only in vitro but also in vivo pharmacological studies.