Mechanism of action of flibanserin, a multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder

Abstract

Flibanserin is a novel multifunctional serotonin agonist and antagonist (MSAA) that improves sexual functioning in premenopausal women who suffer from reduced sexual interest and desire. Take-Home Points' Sexual desire is regulated not only by the sex hormones testosterone and estrogen, but also by the neurotransmitters dopamine and norepinephrine, which enhance sexual interest and desire, and serotonin, which inhibits sexual interest and desire.' Brain circuits that connect the prefrontal cortex (PFC) with limbic pleasure centers theoretically mediate motivation, interest, and desire. These circuits are hypothesized to be the sites of inefficient information processing associated with sexual disorders that are characterized by reduced interest and desire.' The multifunctional serotonergic agent flibanserin is both a serotonin 1A agonist and a serotonin 2A antagonist.Flibanserin theoretically improves sexual functioning by enhancing downstream release of dopamine and norepinephrine while reducing serotonin release in the brain circuits that mediate symptoms of reduced sexual interest and desire.

Development and Syntheses of Flibanserin (Addyi®) - "the Female Viagra®"

“…Assim, acredita-se que esta molécula melhore o desejo sexual aumentando a liberação de dopamina e norepinefrina, acompanhado de redução na liberação de serotonina nos circuitos cerebrais relacionados ao interesse sexual e ao desejo. 15,16 O composto apresenta ainda atividade antidepressiva na maioria dos modelos animais sensíveis a antidepressivos, porém qualitativamente esta atividade parece diferente de outros fármacos desta classe. 17…”

Flibanserin: First Global Approval

“…Agonism and antagonism of postsynaptic 5-HT 1A of 5-HT 2A receptors by flibanserin could potentially lead to downstream alterations in neurotransmitter release that regulate reward processing [18]. These neurotransmitter changes may include increases in dopamine and norepinephrine and reductions in serotonin [18], as has been seen with flibanserin in some instances in the brains of rats, in regions such as the prefrontal cortex [19,20] and hypothalamic medial preoptic area [20]. Indeed, in other rat studies, flibanserin appeared to modulate serotonergic and dopaminergic activity in distinct areas of the brain [21], preferentially activating regions involved in dopaminergic reward (particularly the ventral tegmental area) and the integration of sexual cues (i.e.…”

Next-day residual effects of flibanserin on simulated driving performance in premenopausal women

“…Flibanserin (FLI; Addyi) is a multifunctional serotonin agonist and antagonist that has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women (Addyi Package Insert, ; Joffe et al, ; Stahl, ). HSDD is defined as the persistent lack of sexual desire that causes marked distress or interpersonal difficulty and is not due to (a) a coexisting medical or psychiatric condition, (b) problems within the relationship, or (c) the effects of medication or other drug substance (American Psychiatric Association, ).…”

“…FLI's mechanism of action has not been fully characterized, but its primary pharmacological activity involves the activation of post‐synaptic 5‐HT 1A receptors and inhibition of post‐synaptic 5‐HT 2A receptors (Stahl, ; Stahl, Sommer, & Allers, ). FLI also acts as an antagonist on 5‐HT 2B and 5‐HT 2C receptors and has been shown to have either antagonistic or weak agonist activity on dopamine D 4 receptors (Stahl et al, ).…”