title: Synthesis, biological activity, and conformational analysis of [pGlu6,N-MePhe8,Aib9] substance P (6-11): a selective agonist for the NK-3 receptor.
abstract: A highly potent and selective agonist to the tachykinin NK-3 receptor, [pGlu6,N-MePhe8,Aib9] substance P (6-11) (I), was synthesized via the solid phase method. The ED50 of I was 4 nM in the guinea pig ileum in the absence of atropine (NK-1+NK-3 receptors) and this agonist was 5000-fold less potent in the presence of atropine (NK-1 receptor). The analogue was virtually inactive in the rat vas deferens (NK-2 receptor). A detailed analysis of the solution conformation of this analogue in DMSO-d6 and in a DMSO-d6/H2O cryomixture was carried out by a combination of 1H-nmr 2D techniques (DQF-COSY, TOCSY, NOESY and ROESY) and model building based on empirical energy calculations. Peptide I exists as a mixture of isomers containing cis and trans Phe-N-MePhe peptide bonds. The main isomer, containing a cis Phe-N-MePhe peptide bond, shows a preferred folded conformation characterized by a type VI beta-turn with Phe and N-MePhe in the i + 1 and i + 2 positions. The turn is followed by a helical segment extending to the C-terminal. This conformation is compared to previously reported conformations of other selective tachykinin agonists and may be a promising lead for the design of novel NK-3 agonists with additional conformational constraints.
authors.affiliation: Department of Chemistry, College of Staten Island, CUNY.
authors.forename: M
authors.initials: M
authors.lastname: Tallon
authors.forename: D
authors.initials: D
authors.lastname: Ron
authors.forename: D
authors.initials: D
authors.lastname: Halle
authors.forename: P
authors.initials: P
authors.lastname: Amodeo
authors.forename: G
authors.initials: G
authors.lastname: Saviano
authors.forename: P A
authors.initials: PA
authors.lastname: Temussi
authors.forename: Z
authors.initials: Z
authors.lastname: Selinger
authors.forename: F
authors.initials: F
authors.lastname: Naider
authors.forename: M
authors.initials: M
authors.lastname: Chorev
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000502:physiology*; D018039:Receptors, Tachykinin; D013373:Substance P / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D010446:Peptide Fragments; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; C081943:substance P (6-11), pGlu(6)-N-MePhe(8)-Aib(9)-; D013373:Substance P; D011761:Pyrrolidonecarboxylic Acid