A novel cyclic analog of neuropeptide Y specific for the Y2 receptor

Authors


Correspondence to A. G. Beck-Sickinger, Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, W-7400 Tübingen, Federal Republic of Germany

Abstract

The low-molecular-mass, cyclic analog of neuropeptide Y, [Ahx5–24, γ-Glu2-ɛ-Lys30] NPY (inline image; Ahx, 6-aminohexanoic acid; NPY, neuropeptide Y), was synthesized and investigated for receptor binding, inhibition of forskolin-stimulated cAMP accumulation, inhibition of electrically stimulated rat vas deferens contractions and ability to increase blood pressure. Like the linear peptide [Ahx5–24] NPY (YPSK-Ahx-RHYINLITRQRY), the more rigid, cyclic analog showed good correlation between receptor binding to rabbit kidney membranes and biological activity in the vas deferens assay. Binding of this peptide to a new Y2-receptor-expressing cell line was slightly reduced, compared to the linear peptide [Ahx5–24] NPY, however inhibition of cAMP accumulation was even more efficient.

Unlike the linear peptide [Ahx5–24] NPY, the cyclic analog did not induce a blood pressure increase in rats. Reduced binding to Y1 receptor-expressing SK-N-MC cells, as well as the loss of capability of signal transduction, suggest that only Y2-mediated activity is preserved after cyclization. The selectivity of the cyclic compound for Y2 subtypes of NPY receptors with respect to inhibition of cAMP accumulation is more than fortyfold increased, as compared to the linear NPY-(13–36) peptide, which has been used to determine Y2 selectivity so far.

Ancillary