NPY Y-1 ANTAGONISTS - STRUCTURE-ACTIVITY-RELATIONSHIPS OF ARGININE DERIVATIVES AND HYBRID COMPOUNDS WITH ARPROMIDINE-LIKE PARTIAL STRUCTURES

Previously, omega-guanidino- and omega-aminoalkanamides, structurally derived from arpromidine-like histamine H-2 receptor agonists, were re ported as novel neuropeptide Y Y-1 antagonists. Regardless of the back bone, they resemble BIBP 3226, an argininamide with high NPY Y-1 recep tor affinity and selectivity, with respect to nature and arrangement o f the 'terminal' diaryl, guanidine, and hydroxyphenyl groups. Hybrid c ompounds were synthesized combining the argininamide backbone of BIBP 3226 or partial structures derived from the C-terminal dipeptide of NP Y with characteristic substructures of arpromidine- or amide-type NPY antagonists. Additionally, some analogs of BIBP 3226 with reduced flex ibility were prepared. Structure-activity relationships indicate that, in contrast to alkanamides, homologs and/or isomers of BIBP 3226 with vicinal arrangement of the phenyl rings have decreased Y-1 antagonist ic activity (Ca2+-assay in HEL cells). Replacement of the hydroxybenzy l group by an imidazole ring further decreases activity. It is conclud ed that the binding sites of NPY antagonists with one and with two bas ic groups are not identical. Analogs with a rigid tetrahydro-2-benzaze pine or an indan group in place of the benzyl moiety in BIBP 3226 are active, indicating the role of the OH group and supporting the model p roposed for the interaction of BIBP 3226 with the Y-1 receptor. (C) 19 98 Elsevier Science BN. All rights reserved.