title: Structure-activity studies of neurokinin A.
abstract: A structure-activity study on neurokinin A and its C-terminal fragment NKA (4-10) has been performed in order to find selective agonists for the NK-2 receptor and identify chemical modifications suitable for protecting the peptides from degradation, while maintaining activity. Five series of compounds have been prepared and tested: 1. the complete series of the L-Ala monosubstituted analogues of NKA; 2. a series of NKA fragments from the C- or N-terminal; 3. the complete series of NKA (4-10) analogues monosubstituted with beta-Ala; 4. a series of NKA (4-10) analogues with monosubstitutions in pos. 4, 8, 10 or multisubstitutions in two or more of the same positions; and 5. a series of 6 NKA (4-10) analogues monosubstituted with 1-amino,1-cyclohexane carboxylic acid residue. It has been found that the most selective agonists for the NK-2 receptor system are [beta Ala8]NKA (4-10) and [Nle10]NKA (4-10). Protection from aminopeptidase may be obtained by acetylation of the N-terminal amide of NKA (4-10), while partial protection from endopeptidases should be expected from the presence of beta-Ala in position 8. Conformational constraints induced with 1,amino,1-cyclohexane carboxylic acid residue gave weakly active compounds. Multiple substitutions reduce rather than potentiating the favorable effects of the corresponding monosubstituted compounds.
authors.affiliation: Chemistry Department, A. Menarini Pharmaceuticals, Florence, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Rovero
authors.forename: V
authors.initials: V
authors.lastname: Pestellini
authors.forename: N E
authors.initials: NE
authors.lastname: Rhaleb
authors.forename: S
authors.initials: S
authors.lastname: Dion
authors.forename: N
authors.initials: N
authors.lastname: Rouissi
authors.forename: C
authors.initials: C
authors.lastname: Tousignant
authors.forename: S
authors.initials: S
authors.lastname: Télémaque
authors.forename: G
authors.initials: G
authors.lastname: Drapeau
authors.forename: D
authors.initials: D
authors.lastname: Regoli
mesh_terms: D000818:Animals; D006224:Cricetinae; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D010446:Peptide Fragments; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; D015288:Neurokinin A