Title: Molecule of the Month
Volume: 7
Issue: 10
Author(s): R. Nathan Daniels and Craig W. Lindsley
Affiliation:
Abstract: A new, non-SSRI mechanism of action for Prozac™. Unquestionably, Prozac™ was a landmark drug that redefined the treatment for depression, anxiety disorders, premenstrual syndrome and post-traumatic stress disorder as well as ushering in a wave of new therapies targeting specific serotonin (5-HT) reuptake inhibition (SSRI) [1]. In a recent manuscript (Psychopharmacology 2006, 186, 362-372), Pinna and co-workers report that fluoxetine and its N-desmethyl congener norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake [2]. Pinna further states that the term ‘SSRI’ may be misleading in describing the pharmacological profile of fluoxetine and its congeners and suggests the term ‘selective brain steroidogenic stimulants’ (SBSSs) as a better descriptor [2]. Recently, it has been shown that neurosteroids, such as allopregnanolone (Allo), play critical roles in human brain pathophysiology such as anxiety disorders, premenstrual syndrome, posttraumatic stress disorder, postpartum depression and general depression. For the treatment of major depression, recent clinical trials have indicated that the pharmacological profiles of Prozac™ and related congeners correlate with an increase of Allo in the brain and cerebrospinal fluid. Importantly, Allo is a potent (nM affinity) positive allosteric modulator of gamma-aminobutyric acid (GABA) action at GABAA receptors, potentiating the intensity of GABAgated Cl- currents [3]. Thus, Prozac™ and related analogs increase Allo levels, and subsequent activation of GABAA receptors, at currently prescribed clinical doses which may not block 5-HT reuptake, but does effectively treat depression, premenstrual dysphoria and anxiety [2]. Pinna then explored this hypothesis in animal behavioral models of aggression and anxiety [2]. Their studies found that social isolation in mice is correlated with a down-regulation of Allo content and that pretreatment with Allo abolished aggressiveness as well as correcting the altered responses of GABAA receptors to specific agonists (pentobarbital) and antagonists (picrotoxin). Therefore, drugs capable of upregulating brain Allo content normalize behavioral abnormalities expressed in mice with a downregulation of brain Allo levels. Significantly, Pinna and co-workers discovered that the actions of fluoxetine and norfluoxetine on brain Allo content are stereoselective whereas 5-HT reuptake lacks stereospecificity. Prozac™ is a racemic compound. Pinna found that the EC50s of the (S)-enantiomers of fluoxetine and norfluoxetine to normalize brain Allo levels are 10- and 50-fold lower than those required to inhibit 5-HT reuptake [2]. Will this research herald new drug discovery campaigns aimed at identifying compounds capable of selectively increasing brain Allo levels under the moniker SBSSs? REFERENCES [1] Wong, D.T.; Bymaster, F.P.; Reid, L.R.; Mayle, D.A.; Krushinski, J.H.; Robertson, D.W. Norfluoxetine enetiomers as inhibitors of serotonin uptake in rat brain. Neuropsychopharmacology 1993, 8, 337-344. [2] Pinna, G.; Costa, E.; Guidotti, A. Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake. Psychopharmaology 2006, 186, 362-372. [3] Lambert, J.J.; Belelli, D.; Peden, D.R.; Vardy, A.W.; Peters, J.A. Neurosteroid modualtion of GABBA receptors. Prog. Neurobiol. 2003, 71, 67-80.
