Pharmacodynamics<unk>  is a very selective α2-adrenergic blocker, that readily crosses the blood–brain barrier. Blockade of α2-adrenoreceptors, particularly presynaptic autoreceptors in noradrenergic neurons by<unk> , produces an increase in the synaptic concentrations of noradrenaline, by blocking the autoinhibitory feedback mechanism. This release of noradrenaline has a potential value in the treatment of disorders which are associated with a deficiency of noradrenaline at postsynaptic adrenoreceptors, such as depression, the early features of Alzheimer's disease and schizophrenia and other neurodevelopmental disorders associated with cognitive impairment.<unk>  also exhibits no anticholinergic, antidopaminergic, α1-adrenergic, β-adrenergic, muscarinic, or 5-HT1 receptor-blocking effects.<unk>  showed α2-adrenoceptors antagonist activity in vivo in several animal species. In the conscious mouse,<unk>  was effective by the oral route in preventing clonidine-induced hypothermia and antinociception. While in the rat the marked impairment of rotarod performance were prevented dose-dependently by<unk> .<unk> , orally prevented agonist UK-14304 induced sedation and bradycardia in a dose-related fashion in the dog.<unk>  has been shown to possess central α2-adrenoceptor antagonist activity after both single and repeated oral doses in man, significantly attenuating all responses to the agonist clonidine (growth hormone secretion, bradycardia, hypotension, xerostomia) apart from the measures of sedation.<unk>  has shown positive effects in the treatment of cognitive dysfunction in schizophrenia patients when orally dosed with<unk> , and in the treatment of central neurodegenerative disorders in models of Alzheimer's disease where it prevented age-related decline in spatial working memory in transgenic mice, although it had no effect in other memory tasks such as object recognition or the Morris water maze and occurred in the absence of obvious concomitant change in pathology such as β-amyloid plaque load and astrocytosis. The individual chiral isomers 7 (+) 3aR,9aR and 8 (-) 3aS,9aS of<unk>  both had comparable levels of α2-adrenoceptors antagonist potency and α2/α1 selectivity to racemic<unk>  6 (±) rel 3aR,9aR in vitro and a similar potency in vivo in reversing the hypothermia induced in mice by clonidine. Racemic<unk>  as HCl hemi-hydrate, (+)Enantiomer HCl and (-)EnantiomerHCl Adrenoceptors antagonist potency of racemic<unk>  and enantiomers in vitro and in vivo Compound as HCl α2-AdrenoceptorsVas deferensUK14304 α1-AdrenoceptorsAnococcygeus musclePhenylephrine HypothermiaClonidineMice po Optical Rotation Melting Point Measurement pKB pKB ED50mg/kg α20-23D° mp°C 6 (+/-) rel 3aR,9aR 7.86 5.00 0.66 0 245 7 (+) 3aR,9aR 7.88 4.47 0.73 +159.6 235-236 8 (-) 3aS,9aS 7.68 4.95 0.46 -159.4 238-240 Pharmacokinetics<unk>  has rat and human protein binding of 81-92% and 95% respectively.<unk>  shows high in vitro permeability in MCDK (Papp nm/s =2500) and Caco-2 (Papp nm/s =2000) cells which correlates well with the known high oral intestinal absorption (100%) in humans.<unk>  is well absorbed following oral dosing in all animals. Clearance was largely metabolic, with both oral and intravenous doses being excreted mainly via the urine (> 90%, of administered dose), chiefly as phase II metabolites (sulphamic acid and carbamoyI glucuronide conjugates).<unk>  has high oral bioavailability (100%) and a long duration of action (2hr) in the rat, which accounts for its similar potency seen by both the oral and intravenous routes of administration in this species. The excellent pharmacokinetics exhibited by<unk>  in animals also translated into man where it has a superior bioavailability (97%) and longer duration of action (6-7hrs). Metabolism<unk>  was not metabolized by human cytochrome P450 enzymes CYP1A and CYP2A, and was found not to be a mutagen in cultured human peripheral lymphocytes and did not cause gene mutation when administered to Chinese hamster fibroblasts in culture. No mutagenic potential was identified in microbiological mutagenicity tests including a fluctuation test with S9 activation. No hydroxylated metabolites were identified after incubation with rat liver microsomes (S9) or in rat urine following oral dosing. The compound was well tolerated on repeat oral administration to rat (≤ 200 mg /kg/day) and dog (≤ 80 mg/kg/day) for 12 months.
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