Structure-activity relationship study of R396, an NK2 tachykinin antagonist selective for the NK2B receptor subtype.
We report on a structure-activity study of R396 (Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH2), a linear hexapeptide tachykinin antagonist selective for the putative NK2B receptor subtype. Asp2, Trp4 and the C-terminal glycinamide have been challenged by classical amino acid substitutions with the aim of elucidating the structural requirements responsible for NK2 subtype selectivity. The biological activities indicate that Asp2 has a crucial role for the high affinity of R396 at the NK2B subtype: none of the analogues substituted in position 2 display higher affinity as compared to R396, regardless of the nature of the residue introduced. Trp4 has been replaced by other aromatic residues, again yielding weak antagonist or inactive compounds. Finally, the C-terminal amide appears to be crucial for affinity, the free acid analogue being devoid of biological activity. On the other hand, antagonistic activity is maintained both by the desGly pentapeptide and by the analogue bearing beta Ala in place of Gly in position 6. In conclusion, since the NK2B selectivity pattern was maintained throughout the whole series of R396 replacement analogues, we speculate that the overall conformational features of this family of linear hexapeptides favour the interaction with the NK2B receptor subtype.
Rovero
P
P
CNR, Istituto di Mutagenesi e Differenziamento, Pisa, Italy.
Astolfi
M
M
Manzini
S
S
Jukic
D
D
Rouissi
N
N
Maggi
C A
CA
Regoli
D
D
D000595:Amino Acid Sequence; D000818:Animals; D006224:Cricetinae; D008297:Male; D008647:Mesocricetus; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D018039:Receptors, Tachykinin; D013329:Structure-Activity Relationship; D015320:Tachykinins / Q000037:antagonists & inhibitors*
D009842:Oligopeptides; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; D015320:Tachykinins; C076938:R 396