Berith Bjørnholm

Interference of anaesthetics with radioligand binding in neuroreceptor studies

Evaluations of new emission tomography ligands are usually carried out in animals. In order to keep the animals in a restricted position during the scan session, anaesthesia is almost inevitable. In ex vivo rat studies we investigated the interference of ketamine/xylazine, zoletile mixture, isoflurane and halothane with the serotonin re-uptake site, the serotonin2A receptor and the dopamine re-uptake site by use of [3H]-(S)-citalopram, [18F]altanserin and [125I]PE2I, respectively. Ketamine/xylazine decreased the target-to-background ratio (mean ± SD) of [3H]-(S)-citalopram from 1.5±0.19 to 0.81±0.19 (P<0.05), whereas isoflurane and halothane increased the ratio from 1.5±0.19 to 1.9±0.24 and 2.1±0.13 (P<0.05), respectively. Only with the zoletile mixture did the ratio remain unaltered. None of the tested anaesthetics affected the target-to-background ratio of [18F]altanserin. The [125I]PE2I target-to-background ratio decreased with both ketamine/xylazine (from 12.4±0.81 to 10.1±1.4, P<0.05) and isoflurane (from 12.4±0.81 to 9.5±1.1, P<0.05) treated rats, whereas treatment with zoletile mixture and halothane left the ratio unaltered. It is concluded that prior to performance of neuroreceptor radioligand studies, the possible interaction between radioligands and anaesthetics should be carefully evaluated.

A pharmacophore model for NK2 antagonist comprising compounds from several structurally diverse classes

A neurokinin 2 (NK2) antagonist pharmacophore model has been developed on the basis of five non-peptide antagonists from several structurally diverse classes. To evaluate the pharmacophore model, another 20 antagonists were fitted to the model. By use of exhaustive conformational analysis (MMFFs force field and the GB/SA hydration model) and least-squares molecular superimposition studies, 23 of the 25 antagonists were fitted to the model in a low energy conformation with a low RMS value. The pharmacophore model is described by four pharmacophore elements: Three hydrophobic groups and a hydrogen bond donor represented as a vector. The hydrophobic groups are generally aromatic rings, but this is not a requirement. The antagonists bind in an extended conformation with two aromatic rings in a parallel displaced and tilted conformation. The model was able to explain the enantioselectivity of SR48968 and GR159897.