Tachykinin antagonists: substitutions in positions 5 and 6 with amino acids from the primary sequence of substance P homologues.
A series of tachykinin antagonists has been synthetized by substituting the amino acids of eight naturally occurring tachykinins into the general antagonist [pro4, trp7,9, Phe 11]tachykinin-(4-11). Five decapeptide antagonists were also synthetized. These antagonists were tested on four smooth muscle preparations, the rabbit mesenteric vein, the guinea-pig ileum, the guinea-pig trachea and the rat urinary bladder. On all tissues, except the rat urinary bladder, antagonists that had amino acids other than Gln5 Gln6 found in the substance P molecule were inactive as antagonists, and some had marked intrinsic activity on the guinea-pig ileum and the guinea-pig trachea. The inhibitory activity of these antagonists on the rat urinary bladder, however, was quite marked. The activities of these antagonists on the rat urinary bladder can be summarized as follows: (a) In general decapeptide antagonists were of low affinity. (b) Octapeptide antagonists showed variable affinities against the various tachykinins and some were selective. The only two antagonists which were fairly active against all tachykinins were [pro4, trp7,9, Phe11]SP-(4-11) and [pro4, trp7,9, Phe11] UPE-(4-11). (c) Physalaemin was frequently antagonized in a non-surmountable manner. (d) Eledoisin and kassinin were each inhibited by only one antagonist, and the antagonist was different for each tachykinin. Some tachykinin receptors on smooth muscle have a binding site which is highly selective for Gln5 Gln6, especially if the affinity of antagonists is considered. Another tissue, the rat urinary bladder, does not exhibit this selectivity.(ABSTRACT TRUNCATED AT 250 WORDS)
Mathison
R
R
Escher
E
E
Huggel
H
H
Mizrahi
J
J
Regoli
D
D
D000595:Amino Acid Sequence; D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008642:Mesenteric Veins / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D009479:Neuropeptides; D009842:Oligopeptides / Q000037:antagonists & inhibitors; D011817:Rabbits; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000032:analysis; D018039:Receptors, Tachykinin; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors*; D015320:Tachykinins; D014132:Trachea / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects
D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009842:Oligopeptides; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; D015320:Tachykinins; C045322:phyllomedusin; D013373:Substance P