Toward Labeled Argininamide‐Type NPY Y₁ Receptor Antagonists: Identification of a Favorable Propionylation Site in BIBO3304

Abstract

Aiming at molecular tools for the neuropeptide Y Y1 receptor (Y1 R), three types of derivatives of the argininamide-type Y1 R antagonist BIBO3304 were prepared by (i) propionylation at the guanidine group (3), (ii) substitution at the urea moiety with a propionamidobutyl residue (4), and (iii) replacement of ureidomethyl by a propionylaminomethyl group (5). With Ki and Kb values in the range of 1.5-4.3 nM, determined in binding and functional assays, and high selectivity for the Y1 R over the Y2 R, Y4 R, and Y5 R, compounds 4 and 5 were identified as promising candidates for radiolabeling by [(3) H]propionylation according to established protocols.

High Affinity Agonists of the Neuropeptide Y (NPY) Y4 Receptor Derived from the C-Terminal Pentapeptide of Human Pancreatic Polypeptide (hPP): Synthesis, Stereochemical Discrimination, and Radiolabeling

“…The assay was performed for the functional characterization of selected ligands at the human Y 1 receptor using HEL cells and a LS-50B luminescence spectrometer (PerkinElmer, Überlingen, Germany) as previously described. , …”

“…The assay was performed for the functional characterization of selected ligands at the human Y 1 receptor using HEL cells and a LS-50B luminescence spectrometer (PerkinElmer, U ̈berlingen, Germany) as previously described. 39,40 Aequorin Calcium Assay. The assay was performed on CHO-hY 4 -G qi5 -mtAEQ cells in buffer III as previously described 23 using a GENios Pro plate reader (Tecan, Salzburg, Austria).…”

Nω-Carbamoylation of the Argininamide Moiety: An Avenue to Insurmountable NPY Y1 Receptor Antagonists and a Radiolabeled Selective High-Affinity Molecular Tool ([3H]UR-MK299) with Extended Residence Time

“…Melting points were determined with a Buchi 510 apparatus (Buchi, Essen, Germany) (compounds 10, 13,14,35) or with a Lambda Photometrics Optimelt MPA100 apparatus (Lambda photometrics, Harpenden, UK) (compounds 22, 24−27, 31, 32) and are uncorrected. Specific optical rotations at 589 nm (Na-D line) were measured on a Polarimeter P8000-T equipped with an electronic Peltier thermostat PT31 (A. KRU ̈SS Optronic, Hamburg, Germany) 13 C, 100 MHz) or a Bruker Avance 600 instrument with cryogenic probe (14.1 T; 1 H, 600 MHz; 13 C, 150 MHz) (Bruker, Karlsruhe, Germany).…”

“…Aiming at Y 1 R radioligands with higher affinity, potential radioligands derived from argininamide 1b (BIBO3304) 13 (Figure 1) were recently described. 14 However, derivatization of 1b resulted in a pronounced decrease in Y 1 R affinity, leading to ligands with binding constants in the single-digit nanomolar range. In continuation of our work on argininamide-type Y 1 R antagonists, we focused on N ω -carbamoylated argininamides, as the carbamoylguanidine moiety was recently identified as a stable bioisostere of the acylguanidine group, 12,15,16 conferring higher affinity than the guanidine group in the parent compound 1a, as previously reported for 5−7 17,18 (Figure 1).…”

Heterodimeric Analogues of the Potent Y1R Antagonist 1229U91, Lacking One of the Pharmacophoric C-Terminal Structures, Retain Potent Y1R Affinity and Show Improved Selectivity over Y4R

“…Both small-molecule and peptide-based antagonists have been described for the Y 1 R. Small-molecule argininamide analogues of the NPY C-terminus, typified by compounds such as BIBO3226 ( 2 ) and UR-MK299 ( 3 ), are capable of sub-nanomolar affinity for the Y 1 R. − The development of peptide ligands was initiated by the discovery that the C-terminal NPY decapeptide, Tyr-Ile-Asn-Leu-Ile-Tyr-Arg-Leu-Arg-Tyr-NH 2 , possessed Y 1 R antagonist properties, with structure–activity relationship (SAR) studies confirming that, for the native NPY peptide, Arg, Arg, and Tyr were essential for receptor binding and biological activity of this analogue. Based on this sequence, the subsequent peptide, BVD15 ( 4 , BW1911U90; Ile-Asn-Pro-Ile-Tyr-Arg-Leu-Arg-Tyr-NH 2 ; Figure ), showed increased Y 1 R selectivity over the Y 2 R by 40-fold , and has since been used as the basis for DOTA, NOTA and 18F radiolabelled derivatives. − …”