BIBP-3226, THE FIRST SELECTIVE NEUROPEPTIDE Y1 RECEPTOR ANTAGONIST - A REVIEW OF ITS PHARMACOLOGICAL PROPERTIES

Based on the assumption that the pharmacophoric groups interacting wit h the Y1 receptor are located in the C-terminal part of neuropeptide Y , low molecular weight compounds with high affinity and selectivity fo r the Y1 receptor were designed and synthesized. The prototype BIBP 32 26 possesses affinity for the Y1 receptor in the nanomolar range. In a ddition, this compound is selective displaying rather low affinity for Y2, Y3, Y4 and a set of 60 other receptors. Both biochemical and phar macological studies showed that BIBP 3226 behaves as a competitive ant agonist. Using BIBP 3226 it was possible to investigate the role of NP Y and/or Y1 receptors in blood pressure regulation. The interesting ob servation was that antagonism to Y1 receptors had no major influence o n the basal blood pressure but attenuated stress induced hypertension. This strongly supports the hypothesis that NPY is mainly released dur ing stress involving intense sympathetic nervous system activation. Mo reover, BIBP 3226 can be used to characterize NPY receptor subtypes. F or instance, we were able to show that presynaptic NPY receptors media ting catecholamine release do not solely belong to the Y2 subtype, but that presynaptic Y1 receptors also exist. In conclusion, BIBP 3226 ha s been shown to be an important tool for the elucidation of the physio logical role of Y1 receptors in the cardiovascular system.