title: Synthesis and neuropeptide Y Y1 receptor antagonistic activity of N,N-disubstituted omega-guanidino- and omega-aminoalkanoic acid amides.
abstract: Potent arpromidine-type histamine H2 receptor agonists such as BU-E-76 (He 90481) were among the first non-peptides reported to display weak neuropeptide Y (NPY) Y1 receptor antagonist activity. In search of new chemical leads for the development of more potent NPY antagonists, a series of N,N-disubstituted omega-guanidino and omega-aminoalkanoic acid amides were synthesized on the basis of structure-activity relationships and molecular modeling studies of arpromidine and related imidazolylpropylguanidines. In one group of compounds the imidazole ring was retained whereas in the second group it was replaced with a phenol group representing a putative mimic of Tyr36 in NPY. Although the substitution patterns have not yet been optimized, the title compounds are NPY Y1 antagonists in human erythroleukemia (HEL) cells (Ca2+ assay) achieving pKB values in the range of 6.3-6.6. For representative new substances tested in the isolated guinea pig right atrium histamine H2 receptor agonism could not be found. In the N-(diphenylalkyl)amide series, compounds with a trimethylene chain were more active Y1 antagonists than the ethylene homologs. Concerning the spacer in the omega-amino or omega-guanidinoalkanoyl portion, the best activity was found in compounds with a four- or five-membered alkyl chain or a 1,4-cyclohexylene group. Surprisingly, in contrast to the phenol series, in the imidazole series the compounds with a side chain amino group turned out to be considerably more potent than the correspondence strongly basic guanidines. Thus, the structure-activity relationships appear to be different for the diphenylalkylamide NPY antagonists with one or two basic groups.
authors.affiliation: Institute of Pharmacy, University of Regensburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: S
authors.initials: S
authors.lastname: Knieps
authors.forename: K
authors.initials: K
authors.lastname: Gessele
authors.forename: S
authors.initials: S
authors.lastname: Dove
authors.forename: G
authors.initials: G
authors.lastname: Bernhardt
authors.forename: A
authors.initials: A
authors.lastname: Buschauer
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000595:Amino Acid Sequence; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000577:Amides; D006146:Guanidines; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor