Pharmacology of Flibanserin

Abstract

Flibanserin has preferential affinity for serotonin 5-HT 1A , dopamine D 4 , and serotonin 5-HT 2A receptors. In vitro and in microiontophoresis, flibanserin behaves as a 5-HT 1A agonist, a very weak partial agonist on dopamine D 4 receptors, and a 5-HT 2A antagonist. In vivo flibanserin binds equally to 5-HT 1A and 5-HT 2A receptors. However, under higher levels of brain 5-HT (i.e., under stress), flibanserin may occupy 5-HT 2A receptors in higher proportion than 5-HT 1A receptors. The effects of flibanserin on adenylyl cyclase are different from those of buspirone and 8-OH-DPAT, two other purported 5-HT 1A receptor agonists. Flibanserin reduces neuronal firing rate in cells of the dorsal raphe, hippocampus, and cortex with the CA1 region being the most sensitive in the brain. Flibanserin-induced reduction in firing rate in the cortex seems to be mediated through stimulation of postsynaptic 5-HT 1A receptors, whereas the reduction of the number of active cells seems to be mediated through dopamine D 4 receptor stimulation. Flibanserin quickly desensitizes somatic 5-HT autoreceptors in the dorsal raphe and enhances tonic activation of postsynaptic 5-HT 1A receptors in the CA3 region. Flibanserin preferentially reduces synthesis and extracellular levels of 5-HT in the cortex, where it enhances extracellular levels of NE and DA. Flibanserin displays antidepressant-like activity in most animal models sensitive to antidepressants. Such activity, however, seems qualitatively different from that exerted by other antidepressants. Flibanserin seems to act via direct or indirect stimulation of 5-HT 1A , DA, and opioid receptors in those animal models. Flibanserin does not display consistent effects in animal models of anxiety and seems to exert potential antipsychotic effects. Flibanserin may induce some sedation but does not induce observable toxic effects at pharmacologically relevant doses.Flibanserin behaves as a 5-HT 1A agonist in cloned cells and the cortex and hippocampus of human and rat brain ( Table 2). In the dorsal raphe, flibanserin behaves as an agonist when firing rate was taken as an index of activity in rats (58) but was devoid of agonist activity when forskolin-stimulated cAMP was measured in human tissue (44). In contrast to the dorsal raphe nucleus of rats (24), 5-HT 1A receptors in the dorsal raphe nucleus of humans appears to be linked with adenylyl cyclase (44). In human tissues, the EC 50 of flibanserin in reducing forskolin-stimulated cAMP formation is similar to the affinity values for 5-HT 1A receptors (Table 1 and 2). In contrast, the EC 50 of flibanserin in reducing forskolin-stimulated cAMP formation in cells or rat tissues is different from the affinity values for 5-HT 1A receptors. The coupling system between the receptor and the G-proteins is important to demonstrate activity for agonists (55). Thus, it may be that the relative amount of various G-proteins present in human tissue is different from that present in CHO cells or rat tissue. Flibanserin binds to only one site in human 5-HT 1A ...

Agonist and antagonist properties of antipsychotics at human dopamine D4.4 receptors: G-protein activation and K+ channel modulation in transfected cells

“…Thus bifeprunox, F15063, SLV313 and BP897 exhibited (modest) partial agonist properties whereas the established antipsychotics clozapine, haloperidol, olanzapine and risperidone were devoid of agonist properties, as previously reported (Burnstein et al, 2005 ;Newman-Tancredi et al, 1997a ;Patel et al, 2003). Sarizotan, an antidyskinetic agent, and flibanserin, developed as an antidepressant and antisexual dysfunction drug (Borsini et al, 2002 ;Kuzhikandathil and Bartoszyk, 2006), both exhibited partial agonist properties at hD 4.4 receptors.…”

“…D 4 receptor activation is also relevant to the treatment of sexual dysfunction, a frequently reported side-effect of antipsychotic treatment that can seriously influence treatment outcome in schizophrenia patients (Chue, 2006 ;Ü çok et al, 2007). Compounds possessing D 4 agonist properties, such as ABT724 and flibanserin (a compound also possessing 5-HT 1A receptor agonist activity), are in clinical evaluation for sexual dysfunction (Borsini et al, 2002 ;Brioni and Moreland, 2006).…”

Effects of methylphenidate and MDMA on appraisal of erotic stimuli and intimate relationships

“…Accordingly, the DA and NE transporter inhibitor and antidepressant bupropion, which has less side effects on sexual arousal and libido than serotonergic antidepressants, increased activation of brain regions related to sexual functioning (Abler et al, 2011). Moreover, flibanserin, which enhances NE and DA while reducing 5-HT (Borsini et al, 2002), increased sexual desire in women with hypoactive sexual desire (Katz et al, 2013). Finally, dextroamphetamine and methylphenidate have been reported to reverse the sexually impairing effects of 5-HT transporter blockers and to even enhance sexual arousal and function in female and male patients with depression (Bartlik et al, 1995).…”

The pharmacodynamic effects of combined administration of flibanserin and alcohol

“…[7][8][9] Although antagonist. 13,14 The function of flibanserin at these post-synaptic receptors is hypothesized to increase dopamine and norepinephrine in the prefrontal cortex and decrease serotonin 15,16 ; all three neuromodulators are thought to play key roles in the regulation of sexual arousal and desire. 17 Although most research regarding neurobiological control of the mammalian sexual response has been conducted in animal models, adequate sexual functioning in humans may result from the proper balance of excitatory and inhibitory signals.…”