Loxapine

Loxapine Succinate is a D2DR and D4DR inhibitor, serotonergic receptor antagonist and also a dibenzoxazepine anti-psychotic agent [1].

In vitro: Loxapine was a typical neuroleptic that showed great structural and functional homology to the atypical antipsychotic clozapine. Chronic loxapine treatment was usually associated with extrapyramidal symptoms (EPS). Loxapineexihibited an extremely strong binding affinity fordopamineD4 andserotonin5-HT2receptors, suggesting that both serotonergic and dopaminergic mechanisms contributed to the antipsychotic drug action and EPS associated with loxapine in the treatment of schizophrenia [1]. In frontal cortex of brain in human and bovine, in the presence of Loxapine, [3H]ketanserin bound to 5-HT2 receptor with ki value of 6.2 nM and 6.6 nM, respectively. In comparing competition experiments involving the human membranes, loxapine exihibited the rank order of potency for the various receptors as follows: 5-HT2≥D4>>>D1>D2 [1]. Loxapine administration at 0.2, 2 and 20 μMafter 1 and 3 days of exposure reduced IL-1βand IL-2 secretion by LPS-activated mixed glia cultures. Loxapine also decreased IL-1βand IL-2 secretion in LPS-induced microglia cultures [2].

In vivo: Chronic administration of loxapine(5 mg/kg) in rats for 4 weeks or 10 weeks significantly reduced more than 50% of serotonin (S2) receptor density. Loxapine (5 mg/kg) didn’t change dopamine receptor density but greatly reduced serotonin receptor density by 47% in the brain of rats [3].

References:
[1].  Singh AN1,Barlas C,Singh S,Franks P,Mishra RK. A neurochemical basis for the antipsychotic activity of loxapine: interactions withdopamineD1,D2, D4 andserotonin5-HT2receptorsubtypes.J Psychiatry Neurosci.1996 Jan;21(1):29-35.
[2].  Labuzek K1,Kowalski J,Gabryel B,Herman ZS. Chlorpromazine and loxapine reduce interleukin-1beta and interleukin-2 release by rat mixed glial and microglial cell cultures.Eur Neuropsychopharmacol.2005 Jan;15(1):23-30.
[3].  Lee T,Tang SW. Loxapine and clozapine decreaseserotonin(S2) but do not elevatedopamine(D2)receptornumbers in the rat brain.Psychiatry Res.1984 Aug;12(4):277-85.