Anders Björk

Preclinical pharmacology of FG5893 : a potential anxiolytic drug with high affinity for both 5-HT1A and 5-HT2A receptors

The effects of FG5893 were evaluated by several different methods; rats were used as experimental animals. Receptor binding studies revealed that FG5893 (2-(4-(4,4-bis(4-fluorophenyl)butyl)-1-piperazinyl)-3-pyridinecarboxy lic acid methyl ester) binds with high affinity to both 5-HT1A (Ki = 0.7 nM) and 5-HT2A receptors (Ki = 4.0 nM) but has only low affinity for the 5-HT2C receptor (Ki = 170 nM). FG5893 dose dependently reduced body temperature, and this effect was inhibited by pretreatment with (+/-)-pindolol. FG5893 (0.1 mg/kg) significantly inhibited head twitch behaviour induced by DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) and FG5893 was also a potent inhibitor of ultrasound vocalization in rat pups (0.3 mg/kg) and of a passive avoidance response (0.1 mg/kg) in mature animals. FG5893 inhibited the cage-leaving response and induced part of the 5-HT behavioural syndrome, but only at very high doses (5 and 10 mg/kg, respectively). At increased doses (1 mg/kg), FG5893 also elicited corticosterone release and reduced the immobility time in the forced-swim test (1 mg/kg). Together, these data indicate that the mixed 5-HT1A receptor agonist/5-HT2A receptor antagonist FG5983 is a potent stimulator of presynaptic 5-HT1A receptors but is less active at the postsynaptic site. FG5893 had potent anxiolytic-like effects both on separation-induced ultrasound vocalization in rat pups and on a passive avoidance response. At increased doses, FG5893 possessed an antidepressant-like property.

Interaction of the novel antipsychotic drug amperozide and its metabolite FG5620 with central nervous system receptors and monoamine uptake sites: Relation to behavioral and clinical effects

Behavioral, biochemical, and electrophysiological studies suggest that amperozide affects mesolimbic and mesocortical dopamine neurotransmission. The receptor binding profile of amperozide is discussed and related to behavioral and clinical, i.e., antipsychotic, effects of the drug. As previously reported, amperozide displayed high affinity for serotonin 5-HT2A receptors (Ki = 16 nmol/L), and moderate affinity for striatal dopamine D2 (Ki = 540 nmol/L) and cortical alpha 1-adrenergic receptors (Ki = 172 nmol/L). In the present study amperozide displayed low affinity for several serotonin receptor subtypes as well as for the dopamine D4 receptor transfected in COS7 cells (Ki D4.2 = 769 nmol/L and Ki D4.4 = 384 nmol/L). Amperozide was very weak or did not interact with several other receptor species including adrenergic, histaminergic, muscarinic, benzodiazepine, gamma-aminobutyric acid, amino acid, opiate, and Ca channels; however, amperozide was found to compete for [3H]paroxetine binding for the serotonin transporter in the nanomolar range (Ki = 49 nmol/L). In vitro and in vivo binding potency of amperozide correlates best with behavioral effects, indicating 5-HT2A antagonism, although serotonin uptake inhibition may contribute to the effects of amperozide on dopamine neurotransmission. The metabolite of amperozide, FG5620, displayed 5-10 times lower pharmacologic activity than amperozide. These properties of amperozide may suggest that the antipsychotic effects of amperozide are mediated by 5-HT2A receptors, although 5-HT uptake inhibition and alpha 1-adrenergic receptor-mediated effects may be considered, particularly at higher doses.