Pharmacology profile of F17464, a dopamine D₃ receptor preferential antagonist

F17464 (N-(3-{4-[4-(8-Oxo-8H-[1,3]-dioxolo-[4,5-g]-chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide, hydrochloride) is a new potential antipsychotic with a unique profile. The compound exhibits high affinity for the human dopamine receptor subtype 3 (hD₃) (K_i = 0.17 nM) and the serotonin receptor subtype 1a (5-HT_1a) (K_i = 0.16 nM) and a >50 fold lower affinity for the human dopamine receptor subtype 2 short and long form (hD_2s/l) (K_i = 8.9 and 12.1 nM, respectively). [¹⁴C]F17464 dynamic studies show a slower dissociation rate from hD₃ receptor (t1/2 = 110 min) than from hD_2s receptor (t1/2 = 1.4 min) and functional studies demonstrate that F17464 is a D₃ receptor antagonist, 5-HT_1a 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-HT_1a receptors is demonstrated in displacement studies in the mouse brain. F17464 increases dopamine release in the rat prefrontal cortex and mouse lateral forebrain - dorsal striatum and seems to reduce the effect of MK801 on % c-fos mRNA medium expressing neurons in cortical and subcortical regions. F17464 also rescues valproate induced impairment in a rat social interaction model of autism. All the neurochemistry and behavioural effects of F17464 are observed in the dose range 0.32-2.5 mg/kg i.p. in both rats and mice. The in vitro - in vivo pharmacology profile of F17464 in preclinical models is discussed in support of a therapeutic use of the compound in schizophrenia and autism.