Dirk Van Haver

Permeability of the blood‐brain barrier for atenolol studied by positron emission tomography

Abstract— The permeability of the blood‐brain barrier for atenolol, a hydrophilic β‐adrenergic blocking agent, has been assessed in dogs, by studying the distribution of [11C]atenolol in brain tissue with positron emission tomography. The passage of atenolol into the brain was very limited, but a measurable small net influx into the brain tissues did occur. Osmotic opening of the blood‐brain barrier resulted in a marked increase of the atenolol concentrations in brain tissue. The approach described, with sequential non‐invasive measurements in brain tissue, is applicable to pharmacokinetic studies of atenolol in man.

Biological Activity of CD‐Ring Modified 1α,25‐Dihydroxyvitamin D Analogues: C‐Ring and Five‐Membered D‐Ring Analogues

Nonsteroidal analogues of 1α,25(OH)2D3, lacking either the full five‐membered D ring (C‐ring analogues) or the full six‐membered C ring (D‐ring analogues) are more potent inhibitors of cell proliferation or inducers of cell differentiation than is 1α,25(OH)2D3. Maximal superagonistic activity was seen for the C‐ring analogue with a 24(R)‐hydroxyl group in the side chain [30‐ to 60‐fold the activity of 1α,25(OH)2D3]. The 19‐nor‐16‐ene‐26,27‐bishomo C‐ring analogue showed the best ratio of antiproliferative to calcemic effects (1275‐fold better than 1α,25(OH)2D3 and severalfold better than all vitamin D analogues so far described). The analogues are able to stimulate specific vitamin D‐dependent genes and are active in transfection assays using an osteocalcin promoter VDRE. Low binding affinity to the vitamin D binding protein, differences in metabolism, or affinity for the vitamin D receptor (VDR) are not the most important explanations for the enhanced intrinsic activity. However, the analogues are able to induce conformational changes in the VDR, which makes the VDR‐ligand complex more resistant against protease digestion than is 1α,25(OH)2D3. In contrast to 20‐epimer steroidal vitamin D analogues, 20‐epimer C‐ring analogues were less potent than analogues with a natural C‐20 configuration. In conclusion, several nonsteroidal vitamin D analogues are superagonists of 1α,25(OH)2D3 despite lower receptor affinity and, for the C‐ring analogues, higher flexibility of the side chain; moreover, they have a better selectivity profile than all analogues yet published. (J Bone Miner Res 2000;15;237–252)

Synthesis, biological activity, and conformational analysis of CD-ring modified trans-decalin 1 alpha,25-dihydroxyvitamin D analogs

A novel series of analogs of 1,25-dihydroxyvitamin D3, the hormonally active metabolite of vitamin D3, characterised by the presence of a trans-fused decalin CD-ring system, possesses surprising biological activities in combination with specific structural modifications in the flexible parts of the molecule, when compared with the natural hydrindane derivatives. (1) A large difference in biological activity is observed between the 20-epimeric trans-decalin analogs that follows a pattern opposite to what is usually observed for the natural ring size. (2) Several trans-decalin analogs that are modified in the seco-B-ring region, including previtamin derivatives, possess a pronounced vitamin D-like activity, whereas the corresponding hydrindane derivatives are inactive. The molecular origin of this behavior is still under study.

A Short Intramolecular Diels−Alder Route to Himbacine Derivatives

The intramolecular cycloaddition of 5 yields the unsaturated lactones 17a, 17b, and 17c as three major isomeric adducts. These were further reduced to the corresponding derivatives 21a, 21b, and 21c, which are intermediates for the synthesis of (+)-himbacine and stereoisomers thereof. Precursor 5 was obtained in a short convergent way using Sonogashira and Stille coupling reactions as the main C−C bond construction reactions.

The development of CD-ring modified analogs of 1α,25-dihydroxyvitamin D

During a 20-year collaboration the laboratories of UGent and KU Leuven have developed different series of Vitamin D analogs characterized by structural modifications in the central CD-ring system. Modifications have first involved the introduction of substituents at C11 and the epimerization at C14, and subsequently more drastic changes consisting in both ring deletion and enlargement relative to the natural CD-ring system. Lately, the focus has shifted towards the synthesis of analogs featuring a symmetrical CD-ring core. As an illustration two different series are presented.

Synthesis and affinity studies of himbacine derived muscarinic receptor antagonists.

A series of himbacine (1)-related analogues has been prepared featuring three different isomeric configurations with respect to the B-ring (a, b and natural c) and three different interconnecting two-carbon unsaturated units [natural (E)-ene, (Z)-ene, and yne]. The study of the binding affinities of the nine resulting compounds, including synthetic (+)-himbacine (3c), towards the M(1)-M(4) muscarine receptor subtypes revealed that analogues 3a and 5c display a promising 10-fold selectivity for the M(2) receptor as compared to the M(1) receptor.

Biological activity and conformational analysis of C20 and C14 epimers of CD-ring modified trans-decalin 1α,25-dihydroxyvitamin D analogs

In the context of our ongoing study of vitamin D structure-function relationships and in an attempt to obtain a better dissociation of their prodifferentiating (HL-60) and/or antiproliferative (MCF-7) activities and their calcemic activity, further 20-epi and 14-epi modifications were made to three trans-decalin CD-ring analogs of 1,25-dihydroxyvitamin D(3), the hormonally active metabolite of vitamin D(3), possessing a natural 20R side chain and featuring additional structural modifications in the seco-B-ring and in the A-ring. Following a previously observed trend and in agreement with the conformational analysis results, all three 20-epi derivatives show substantially lower biological activities, opposite to what is usually observed for analogs having the natural CD-ring. The 14-epi modification (cis-decalins) has little effect on the biological activity of the ynediene type and the saturated derivative, but results in an approximate 10-fold reduction in activity of the previtamin derivative. No better dissociation of the prodifferentiating and/or antiproliferative activities and the calcemic activity was achieved.

11-fluoro-1α-hydroxyvitamin D3: The quest for experimental evidence of the folded vitamin D conformation

Abstract In order to investigate the folded vitamin D conformation in solution, 11-fluorinated vitamin D 3 derivatives have been synthesized by fluorination of the corresponding 11-hydroxy derivatives using FAR and DAST. From 1 H-NMR analysis no conclusive evidence could be drawn for the presence of the folded form in solution.

Study with Positron Emission Tomography of the Osmotic Opening of the Dog Blood‐Brain Barrier for Quinidine and Morphine

Abstract— A canine model was used to evaluate the possibilities offered by positron emission tomography (PET) for the study of drug distribution in the brain during altered states of the blood‐brain barrier (BBB). PET was used to monitor the changes in the distribution of [11C]quinidine and [11C]morphine resulting from BBB‐disruption by intracarotid infusion of a hyperosmolar mannitol solution. Injection of Evans blue dye allowing post‐mortem evaluation of the degree of BBB‐opening was used as a reference method. Brain radioactivity concentrations observed after i.v. injection of either [11C]quinidine or [11C]morphine were markedly increased by intracarotid mannitol infusion, whereas they were not affected by saline infusion. For both drugs a close correlation was found between the radioactivity concentrations and the degree of Evans blue staining within the brain hemispheres and within smaller regions of interest corresponding to quadrants of a hemisphere. This parallelism between the findings for radioactivity concentrations and Evans blue staining suggests that PET allows the detection of in‐vivo changes in brain distribution of drugs resulting from alterations of the BBB permeability.

On the Unexpected Stereochemical Outcome of the Magnesium in Methanol – Conjugate Reduction of an Exocyclic α,β‐Unsaturated Ester

The conjugate reduction of the exocyclic α,β-unsaturated ester 9 with magnesium in methanol gives a mixture of diastereoisomers containing predominantly the less stable 10a. Eventual structural identification rests on the X-ray diffraction analysis of tosylate 18.