SYNTHESIS AND NEUROPEPTIDE-Y Y-1 RECEPTOR ANTAGONISTIC ACTIVITY OF N,N-DISUBSTITUTED OMEGA-GUANIDINOIC AND OMEGA-AMINOALKIANOIC ACID-AMIDES

Potent arpromidine-type histamine H-2 receptor agonists such as BU-E-7 6 (He 90481) were among the first non-peptides reported to display wea k 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 omega-guanidino and omega-aminoalkanoic acid amides were synthesized on the basis of structure-activity relat ionships and molecular modeling studies of arpromidine and related imi dazolylpropylguanidines. 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 s ubstitution patterns have not yet been optimized, the title compounds are NPY Y-1 antagonists in human erythroleukemia (HEL) cells (Ca2+ ass ay) achieving pK(B) values in the range of 6.3 - 6.6. For representati ve new substances tested in the isolated guinea pig right atrium hista mine H-2 receptor agonism could not be found. In ''the N-(diphenylalky l)amide series, compounds with a trimethylene chain were more active Y -1 antagonists than the ethylene homologs. Concerning the spacer in th e omega-amino or omega-guanidinoalkanoyl portion, the best activity wa s found in compounds with a four- or five-membered alklyl chain or a 1 ,4-cyclohexylene group, Surpris ingly, in contrast to the phenol serie s, in the imidazole series the compounds with a side chain amino group turned out to be considerably more potent than the corresponding stro ngly basic guanidines. Thus, the structure-activity relationships appe ar to be different for the diphenylalkylamide NPY antagonists with one or two basic groups.