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Synthesis and Neuropeptide Y Y 1 Receptor Antagonistic Activity of N,N ‐Disubstituted ω‐Guanidino‐ and ω‐Aminoalkanoic Acid Amides
Author(s) -
Müller Manfred,
Knieps Sebastian,
Geßele Karin,
Dove Stefan,
Bernhardt Günther,
Buschauer Armin
Publication year - 1997
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.19973301104
Subject(s) - chemistry , stereochemistry , histamine , neuropeptide y receptor , imidazole , amide , receptor , biological activity , amino acid , antagonist , structure–activity relationship , chemical synthesis , neuropeptide , in vitro , biochemistry , biology , endocrinology
Potent arpromidine‐type histamine H 2 receptor agonists such as BU‐E‐76 (He 90481) were among the first non‐peptides reported to display weak neuropeptide Y (NPY) Y 1 receptor antagonist activity. In search of new chemical leads for the development of more potent NPY antagonists, a series of N,N ‐disubstituted ω‐guanidino and ω‐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 Tyr 36 in NPY. Although the substitution patterns have not yet been optimized, the title compounds are NPY Y 1 antagonists in human erythroleukemia (HEL) cells (Ca 2+ assay) achieving p K B values in the range of 6.3–6.6. For representative new substances tested in the isolated guinea pig right atrium histamine H 2 receptor agonism could not be found. In the N ‐(diphenylalkyl)amide series, compounds with a trimethylene chain were more active Y 1 antagonists than the ethylene homologs. Concerning the spacer in the ω‐amino or ω‐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 corresponding strongly basic guanidines. Thus, the structure‐activity relationships appear to be different for the diphenylalkylamide NPY antagonists with one or two basic groups.