Wolfhard Engel

Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist

Calcitonin gene‐related peptide (CGRP) is one of the most potent endogenous vasodilators known. This peptide is increased during migraine attacks and has been implicated in the pathogenesis of migraine headache. Here we report on the first small molecule selective CGRP antagonist: BIBN4096BS. In vitro, this compound is extremely potent at primate CGRP receptors exhibiting an affinity (Ki) for human CGRP receptors of 14.4±6.3 (n=4) pM. In an in vivo model, BIBN4096BS in doses between 1 and 30 μg kg−1 (i.v.) inhibited the effects of CGRP, released by stimulation of the trigeminal ganglion, on facial blood flow in marmoset monkeys. It is concluded that BIBN4096BS is a potent and selective CGRP antagonist.

The first highly potent and selective non-peptide neuropeptide Y Y1 receptor antagonist: BIBP3226.

The design and subsequent in vitro and in vivo biological characterisation of the first potent and selective non-peptide neuropeptide Y Y1 receptor antagonist, BIBP3226 ((R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-argininami de) is reported. BIBP3226 displaced 125I-labelled neuropeptide Y with high affinity (Ki = 7 nM) from the human neuropeptide Y Y1 receptor and proved to be highly selective. BIBP3226 displayed potent antagonistic properties both in in vitro and in vivo models and thus represents the first selective non-peptide neuropeptide Y Y1 receptor antagonist.

BIIE0246: A selective and high affinity neuropeptide Y Y2 receptor antagonist

The in vitro biological characterisation of the first potent and selective non-peptide neuropeptide Y Y(2) receptor antagonist, (S)-N(2)-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6h)-oxodibenz[b, e]azepin-11-yl]-1-piperazinyl]-2-oxoethyl] cylopentyl] acetyl]-N-[2-[1,2-dihydro-3,5(4H)-dioxo-1,2-diphenyl-3H-1,2, 4-triazol-4-yl]ethyl]-argininamid (BIIE0246) is reported. BIIE0246 displaced [125I]neuropeptide Y with high affinity (IC(50)=3.3 nM) from the human neuropeptide Y Y(2) receptor and proved to be highly selective. BIIE0246 displayed antagonistic properties and thus represents the first selective non-peptide neuropeptide Y Y(2) receptor antagonist.

Structure and physicochemical properties of meloxicam, a new NSAID

Abstract The physicochemical properties of meloxicam, a new NSAID, were investigated. Dependent on pH and solvents used, X-ray crystallography showed that meloxicam crystallized in four different prototropic forms; the anion, the acidic enol, the zwitterion and the cation forms. As determined by 1H- and 13C-NMR, meloxicam in neutral or weakly basic solution exists in the anion form. An equilibrium between the enol and zwitterion forms, dependent upon solvent polarity, was indicated. Meloxicam was soluble at neutral pH but became rapidly insoluble with decreasing pH. At very low pH its solubility increased, indicating a second pKa value and the existen of a cation species. The very low solubility of meloxicam in acidic environments suggests it may cause few local gastrointestinal adverse events. The n-octanol-water partition coefficients (log P values) of meloxicam and other NSAIDs were estimated. At low pH meloxicam was more lipophilic than piroxicam or tenoxicam and similar to ketoprofen and naproxen.

BIBP 3226, the first selective neuropeptide Y1 receptor antagonist: A review of its pharmacological properties

Based on the assumption that the pharmacophoric groups interacting with the Y1 receptor are located in the C-terminal part of neuropeptide Y, low molecular weight compounds with high affinity and selectivity for the Y1 receptor were designed and synthesized. The prototype BIBP 3226 possesses affinity for the Y1 receptor in the nanomolar range. In addition, this compound is selective displaying rather low affinity for Y2, Y3, Y4 and a set of 60 other receptors. Both biochemical and pharmacological studies showed that BIBP 3226 behaves as a competitive antagonist. Using BIBP 3226 it was possible to investigate the role of NPY and/or Y1 receptors in blood pressure regulation. The interesting observation was that antagonism to Y1 receptors had no major influence on the basal blood pressure but attenuated stress induced hypertension. This strongly supports the hypothesis that NPY is mainly released during stress involving intense sympathetic nervous system activation. Moreover, BIBP 3226 can be used to characterize NPY receptor subtypes. For instance, we were able to show that presynaptic NPY receptors mediating catecholamine release do not solely belong to the Y2 subtype, but that presynaptic Y1 receptors also exist. In conclusion, BIBP 3226 has been shown to be an important tool for the elucidation of the physiological role of Y1 receptors in the cardiovascular system.

Labeling of neuropeptide Y receptors in SK-N-MC cells using the novel, nonpeptide Y1 receptor-selective antagonist [3H]BIBP3226

The binding of tritium-labelled BIBP3226, N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]-D-arginine amide, to human neuroblastoma SK-N-MC cells was investigated. [3H]BIBP3226 reversibly binds to neuropeptide Y receptors of the Y1 subtype expressed in SK-N-MC cells with a KD of 2.1 +/- 0.3 nM (mean +/- S.E.M., n = 3) and a Bmax of 58,400 +/- 1100 sites/cell. Non-specific binding did not exceed 30% of the total radioactivity bound at KD. In competition experiments [3H]BIBP3226 is concentration-dependently displaced by neuropeptide Y and its peptide analogues with an affinity pattern neuropeptide Y = [Leu31, Pro34]neuropeptide Y >> neuropeptide Y-(18-36). This rank order of potencies is consistent with the interaction of [3H]BIBP3226 with neuropeptide Y receptors of the Y1 subtype. Therefore, [3H]BIBP3226 can be used as selective ligand to study neuropeptide Y Y1 receptors.

Characterization of BIBN 99: a lipophilic and selective muscarinic M2 receptor antagonist.

The present study was designed to characterize the receptor selectivity profile of the novel muscarinic M2 receptor antagonist BIBN 99 (5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1- oxopentyl)ethylamino]propyl]-1-piperidinyl]acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one). In radioligand binding studies BIBN 99 showed high affinity for m2/M2 sites (pKi = 7.52/7.57), intermediate affinity for m4 sites (pKi = 6.76) and low affinity for m1/M1 (pKi = 5.97/6.17), m3/M3 (pKi = 6.11/6.04) and m5 sites (pKi = 5.84). Functional studies in vitro showed BIBN 99 to be a competitive antagonist and to have an 11- to 25-fold higher affinity for M2 receptors than for putative M1 receptors in the rabbit vas deferens or M3 receptors in guinea-pig trachea. In vivo studies revealed that BIBN 99 is able to cross the blood-brain barrier, and although showing an approximately 3-fold higher affinity for M2 binding sites BIBN 99 appeared to be 7- to 18-fold less potent than AF-DX 116 in inhibiting muscarinic agonist or vagally induced bradycardia in rats and guinea-pigs. The results show that BIBN 99 is the first lipophilic muscarinic M2 receptor antagonist to have remarkable M2 versus M1 selectivity (30-fold). In addition, BIBN 99 possesses central nervous system activity and only minor peripheral cardiac effects.

BIBP 3226, a potent and selective neuropeptide Y Y1-receptor antagonist. Structure-activity studies and localization of the human Y1 receptor binding site

Publisher Summary This chapter discusses the design of BIBP 3226, a highly potent and selective nonpeptide Y1 antagonist, and its interaction with the human Y1 receptor based on structure-activity studies and receptor mutation work. A detailed model for the interaction of BIBP 3226 with the hY1-receptor is developed using a Y1-receptor model and a three-dimensional model of BIBP 3226. A cation-π-interaction of the guanidino group of BIBP 3226 with F286 and a π–π-interaction of the benzene rings of the diphenylacetyl moiety of BIBP 3226 with the benzene rings of F173 and Y211 is suggested in the model. In order to investigate the NPY antagonistic properties in vitro, the ability of BIBP 3226 to antagonize the pressor response elicited by intravenous administration of NPY in the pithed rat was examined. It is found that BIBP 3226 reduced the pressor response induced by cold stress and normalized the cardiovascular changes. It is found that that NPY and Y1 receptors play a significant role in the regulation of vascular tone during stress.