Role of D-tryptophan for affinity of MEN 10207 tachykinin antagonist at NK2 receptors.
The role of the D-Trp residues in the sequence of the NK2-selective tachykinin antagonist, MEN 10207 (Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg-NH2). has been examined by replacement of each D-Trp with either the L-isomer or the residue naturally occurring in the same position of neurokinin A(4-10). The biological activity of the analogues thus obtained has been characterized, with special attention to the selectivity for the three tachykinin receptors and for the two subtypes of the NK2 receptor recently described. We conclude that the simultaneous presence of the three D-Trp residues of MEN 10207 is crucial both for affinity and for selectivity.
Rovero
P
P
Chemistry Department, A. Menarini Pharmaceuticals, Firenze, Italy.
Astolfi
M
M
Renzetti
A R
AR
Patacchini
R
R
Giachetti
A
A
Maggi
C A
CA
D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D006224:Cricetinae; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007536:Isomerism; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008647:Mesocricetus; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D015288:Neurokinin A / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D018039:Receptors, Tachykinin; D013329:Structure-Activity Relationship; D015320:Tachykinins / Q000378:metabolism; D014132:Trachea / Q000187:drug effects / Q000502:physiology; D014364:Tryptophan
D009842:Oligopeptides; D010446:Peptide Fragments; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; D015320:Tachykinins; C063615:neurokinin A (4-10), Tyr(5)-Trp(6,8,9)-Arg(10)-; D015288:Neurokinin A; D014364:Tryptophan