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- Varnäs, K., et al.
(author)
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Integrated strategy for use of positron emission tomography in nonhuman primates to confirm multitarget occupancy of novel psychotropic drugs : An example with AZD3676
- 2016
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In: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology and Experimental Therapy. - 0022-3565 .- 1521-0103. ; 358:3, s. 464-471
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Journal article (peer-reviewed)abstract
- Positron emission tomography (PET) is widely applied in central nervous system (CNS) drug development for assessment of target engagement in vivo. As the majority of PET investigations have addressed drug interaction at a single binding site, findings of multitarget engagement have been less frequently reported and have often been inconsistent with results obtained in vitro. AZD3676 [N,N-dimethyl-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl) benzofuran-2-carboxamide] is a novel combined serotonin (5- hydroxytryptamine) 5-HT1A and 5-HT1B receptor antagonist that was developed for the treatment of cognitive impairment in Alzheimer's disease. Here, we evaluated the properties of AZD3676 as a CNS drug by combining in vitro and ex vivo radioligand binding techniques, behavioral pharmacology in rodents, and PET imaging in nonhuman primates. Target engagement in the nonhuman primate brain was assessed in PET studies by determination of drug-induced occupancy using receptorselective radioligands. AZD3676 showed preclinical properties consistent with CNS drug potential, including nanomolar receptor affinity and efficacy in rodent models of learning and memory. In PET studies of the monkey brain, AZD3676 inhibited radioligand binding in a dose-dependent manner with similar affinity at both receptors. The equally high affinity at 5-HT1A and 5-HT1B receptors as determined in vivo was not predicted from corresponding estimates obtained in vitro, suggestingmore than 10-fold selectivity for 5-HT1A versus 5-HT1B receptors. These findings support the further integrated use of PET for confirmation of multitarget occupancy of CNS drugs. Importantly, earlier introduction of PET studies in nonhuman primates may reduce future development costs and the requirement for animal experiments in preclinical CNS drug development programs.
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- Mellander, S, et al.
(author)
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Neural beta-adrenergic dilatation of the facial vein in man. Possible mechanism in emotional blushing
- 1982
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In: Acta Physiologica Scandinavica. - 0001-6772. ; 114:3, s. 393-399
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Journal article (peer-reviewed)abstract
- Ring preparations of the superficial buccal segment of the human facial vein, taken from extirpated tissue in 12 patients during neck surgery, were studied in vitro. The vein developed a maintained intrinsic myogenic tone in response to passive stretch and was supplied with alpha- as well as beta-adrenoceptors, both of which could be influenced by transmural nerve stimulation (TNS) and noradrenaline. These unusual characteristics for a vein are basically similar to the ones described for the rabbit facial vein by Pegram, Bevan & Bevan (1976). In man there seemed to be an inter-individual difference with regard to the abundance of 'innervated' alpha- and beta-adrenoceptors. Facial vein specimens from some subjects thus responded with prompt and pronounced net dilatation to TNS with maximum at 4 Hz and those from others with net constriction with maximum at 16 Hz. The latter showed a reversal into neural beta-adrenergic dilatation after alpha-adrenergic blockade. The human external jugular vein was devoid of intrinsic tone and beta-adrenoceptors. It is tentatively proposed that a beta-adrenergic neuro-effector mechanism in superficial ramifications of the facial vein in man might be involved in the emotional blushing reaction.
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