Title: Pharmacology profile of f17464, a dopamine D3 receptor preferential antagonist potential antipsychotic

Abstract

F1 7 4 6 4 ( N - ( 3 - { 4 - [ 4 - ( 8 - O x o - 8 H - [ 1 , 3 ] - d i o x o l o - [ 4 , 5 - g ] - c h r o m e n - 7 - y l ) - b u t y l ] - p i p e r a z i n - 1 - y l } - p h e n y l ) - methanesulfonamide, hydrochloride) is a new potential antipsychotic with D3 over D2 dopamine receptor preferential antagonism and 5-HT1A receptor partial agonism properties. Its selective D3 receptor occupancy has been demonstrated in a human PET imaging study (Slifstein et al., 2020 Psychopharmacology , 237:519-527). Reported F17464 behavioural work (Sokoloff and Le Foll, 2017 Eur J Neurosci 45(1):2-19.) has been here expanded to show the compound target engagement, neurochemical properties , effects on NMDA - glutamatergic alterations and its beneficial effects in a rodent model for autism (Cosi et al., 2021 Eur J Pharmacol890:173635). F17464 exhibits high affinity for human dopamine receptor subtype 3 (hD3) (Ki = 0.17 nM) and the serotonin receptor subtype 1A (5-HT1A) (Ki = 0.16 nM) and a >50 fold lower affinity for the human dopamine receptor subtype 2 short and long form (hD2s/l) (Ki = 8.9 and 12.1 nM, respectively). [14C]F17464 has a slower dissociation rate from hD3 receptor (t1/2 = 110 min) than from hD2s receptor (t1/2 = 1.4 min) and functional studies demonstrate that F17464 is a D3 receptor antagonist, 5-HT1A receptor partial agonist. In human dopaminergic neurons F17464 blocks ketamine induced morphological changes, an effect D3 receptor mediated. In vivo F17464 target engagement of both D2 and 5-HT1a receptors is demonstrated in displacement studies in the mouse brain. F17464 increases dopamine release in the rat prefrontal cortex and mouse dorsal striatum, frontal cortex, n.accumbens, olfactory tubercle and attenuates the MK801-induced decrease of c-fos mRNA in c-fos medium expressing neurons in mouse cortical and subcortical regions. F17464 also rescues valproate induced impairment in a rat social interaction model of autism. F17464 dose range used both in rats and mice was 0.32– 2.5 mg/kg i.p. The preferential D3 antagonist F17464, is potential antipsychotic that shows promise for treating the cognitive and negative symptoms of schizophrenia and possibly of autism.