title: Application of the guanidine-acylguanidine bioisosteric approach to argininamide-type NPY Y₂ receptor antagonists.
abstract: Strongly basic groups such as guanidine moieties are crucial structural elements, but they compromise the drug-likeness of numerous biologically active compounds, including ligands of G-protein-coupled receptors (GPCRs). As part of a project focused on the search for guanidine bioisosteres, argininamide-type neuropeptide Y (NPY) Y₂ receptor (Y₂R) antagonists related to BIIE0246 were synthesized. Starting from ornithine derivatives, N(G) -acylated argininamides were obtained by guanidinylation with tailor-made mono-Boc-protected N-acyl-S-methylisothioureas. The compounds were investigated for Y₂R antagonism (calcium assays), Y₂R affinity, and NPY receptor subtype selectivity (flow cytometric binding assays). Most of the N(G) -substituted (S)-argininamides showed Y₂R antagonistic activities and binding affinities similar to those of the parent compound, whereas N(G)-acylated or -carbamoylated analogues with a terminal amine were superior (Y₂R: K(i) and K(B) values in the low nanomolar range). This demonstrates that the basicity of the compounds, although 4-5 orders of magnitude lower than that of guanidines, is sufficient to form key interactions with acidic amino acids of the Y₂R. The acylguanidines bind with high affinity and selectivity to Y₂R over the Y₁, Y₄, and Y₅ receptors. As derivatization of the amino group is tolerated, these compounds can be considered building blocks for the preparation of versatile fluorescent and radiolabeled pharmacological tools for in vitro studies of the Y₂R. The results support the concept of bioisosteric guanidine-acylguanidine exchange as a broadly applicable approach to retain pharmacological activity despite decreased basicity.
authors.affiliation: Institut für Pharmazie, Pharmazeutische/Medizinische Chemie II, Universität Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany.
authors.forename: Nikola
authors.initials: N
authors.lastname: Pluym
authors.forename: Albert
authors.initials: A
authors.lastname: Brennauer
authors.forename: Max
authors.initials: M
authors.lastname: Keller
authors.forename: Ralf
authors.initials: R
authors.lastname: Ziemek
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pop
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
mesh_terms: D000215:Acylation; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005434:Flow Cytometry; D019791:Guanidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; C069339:argininamide; D001120:Arginine; D019791:Guanidine