Cyclic peptides as selective tachykinin antagonists.
Twenty homodetic cyclic peptides based on the C-terminal sequence of substance P were prepared (Table I) by a combination of solid-phase techniques and cyclizations using azide coupling procedures. Incorporation of dipeptide mimics based on substituted gamma-lactams were used in some cases to restrict their conformational mobility. Five of these cyclic peptides were shown to have high tachykinin antagonist activity (pA2 > 6) at NK-2 receptors (rat vas deferens). The two most potent of this series, XVII, cyclo(Gln-Trp-Phe-Gly-Leu-Met) (pA2 = 8.1), and I cyclo(Gln-Trp-Phe(R)Gly[ANC-2]Leu-Met) (pA2 = 6.7), were selective for NK-2 receptors compared with the other tachykinin receptors (Table II).
Williams
B J
BJ
Merck Sharp and Dohme Research Laboratories, Harlow, Essex, England.
Curtis
N R
NR
McKnight
A T
AT
Maguire
J J
JJ
Young
S C
SC
Veber
D F
DF
Baker
R
R
D000595:Amino Acid Sequence; D000818:Animals; D006168:Guinea Pigs; D008297:Male; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives; D015320:Tachykinins / Q000037:antagonists & inhibitors*; D014649:Vas Deferens / Q000187:drug effects
D010456:Peptides, Cyclic; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; D015320:Tachykinins; D013373:Substance P