Dimeric argininamide-type neuropeptide Y receptor antagonists: Chiral discrimination between Y1 and Y4 receptors

Carbaboranylation of Truncated C‐Terminal Neuropeptide Y Analogue Leads to Full hY1 Receptor Agonism

“…The adamantyl substitution completely mimicked the potency and maximum response of the carbaboranylated peptide (Figure A). As short peptide analogues of NPY were reported to be active at the related hY 4 R, we also investigated signalling at this receptor (Figure B). Although all of these peptides were able to activate hY 4 R, it was only at very high concentrations, which led to selectivity for hY 1 R over hY 4 R for all modified truncated analogues ranging from 4.4‐fold selectivity for Phe‐sNPY to 237‐fold selectivity for Lau‐sNPY.…”

“…[6] Substitution of the N e -amino group of the Lyss ide chain led to improved potencies in all cases relative to sNPY.T here is ac lear correlation between hydrophobicity and potencyf or the truncated analogues, and the phenyls ubstitution is the least active one and the lauroyl chain is the most active one, resembling NPY activity.T he adamantyl substitution completely mimicked the potencya nd maximum response of the carbaboranylated peptide (Figure 2A). As short peptide analogueso fN PY were reported to be active at the relatedh Y 4 R, [11] we also investigated signalling at this receptor ( Figure 2B). Althougha ll of these peptides were able to activate hY 4 R, it was only at very high concentrations, which led to selectivityf or hY 1 Ro ver hY 4 Rf or all modified truncated analogues ranging from 4.4-fold selectivity for Phe-sNPY to 237-fold selectivity for Lau-sNPY.…”

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

“…The N G ‐propionylated argininamide 3 was prepared by propionylation of building block 6 at the guanidine group and subsequent treatment with trifluoroacetic acid (TFA) to remove the N G ‐Boc group (Scheme ). Treatment of amine precursor 8 with succinimidyl propanoate ( 7 ) gave the potential radioligand 4 (Scheme ).…”

“…Argininamide 1 was the first highly selective Y 1 R antagonist with an affinity in the single‐digit nanomolar range, and its derivatization led to radio, fluorescent, and bivalent Y 1 R ligands . By contrast, the structurally closely related argininamide BIBO3304 ( 2 ) (Fig.…”

“…A) reported to exhibit sub‐nanomolar Y 1 R affinity (IC 50 = 0.38 , K i = 0.25 nM ), has not been exploited for the preparation of pharmacological tools such as radio or fluorescence ligands. Recently, the dimerization of argininamide 2 via spacers attached at the guanidine or the urea moiety yielded bivalent Y 1 R antagonists with markedly lower affinities ( K i 200–330 nM) , suggesting that large substituents are not well tolerated at these positions. In this work, the structure of 2 was modified to explore if propionylation is tolerated and in which position derivatization is most favorable (variants I–III, Fig.…”