Fluoxetine, structure

Fluoxetine hydrochloride (Prozac) is a widely prescribed antidepressant drug introduced by Eh Lilly Co in 1986 It differs from Compound A in having an —NHCH3 group in place of —N(CH3)2 What IS the structure of Prozac" ... 

Description of Method. Fluoxetine, whose structure is shown in Figure 12.31a, is another name for the antidepressant drug Prozac. The determination of fluoxetine and its metabolite norfluoxetine. Figure 12.31 b, in serum is an important part of monitoring its therapeutic use. The analysis is complicated by the complex matrix of serum samples. A solid-phase extraction followed by an HPLC analysis using a fluorescence detector provides the necessary selectivity and detection limits. 

SSRI structurally related to fluoxetine with a shorter half-life, was reported to be an effective and generally well-tolerated treatment for men with moderate-to-severe PE in clinical trial [13,14],... 

Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. 

Olanzapine (Zyprexa). The olanzapine molecule is structurally very similar to clozapine and therefore exerts very similar effects on brain receptors. The dose range of olanzapine for treating schizophrenia is from 5 to 30mg/day. Like clozapine, olanzapine appears to treat both positive and negative symptoms. It is also approved for the treatment of the manic phase of bipolar disorder. It has also been shown to augment the antidepressant effects of fluoxetine in refractory patients. 

Bupropion is an a-aminoketone that is structurally related to amphetamines, and it exhibits unique activity comparable to that of other antidepressants. It is believed that bupropion restores the total amount of norepinephrine in the body. This compound is a poor reuptake inhibitor of dopamine, and does not exhibit anticholinergic activity or inhibit MAO. Its efficacy as an antidepressant is comparable to that of tricyclic antidepressants, and as a serotonin uptake inhibitor it is comparable to fluoxetine. It is preferable to use amoxapine. Synonyms of bupropion are amphebutamon and wellbutrin. 

Atomoxetine (Straterra , originally tomoxetine or tomoxetin, 3) was first described and synthesized by chemists at Eli Lilly in the late 1970s and was one of the few compounds that was known to display meaningful selectivity for the norepinephrine reuptake transporter (NET) versus the serotonin reuptake transporter (SERT) and the dopamine reuptake transporter (DAT) (Barnett, 1986 Molloy and Schmiegel, 1997). Atomoxetine was one of several structurally related and commercially successful monoamine reuptake inhibitors that were developed by Lilly for the treatment of various psychiatric disorders (Eig. 17.4). Fluoxetine (43) and duloxetine (44) have both gained approval in the United States as Prozac and Cymbalta , respectively, and nisoxetine (45) is widely used as a tool in biology. 

Many compounds have been evaluated for their effects on brain metabolism (London, 1993). A surprisingly limited number of common regional metabolic effects have been seen within drug classes. Antipsychot ics, especially the older typical antipsychotics, tend to be associated with changes in striatal metabolism consistent with the high density of D2 dopamine receptors in those brain structures (Cohen et al.. 1999). On the other hand, quite different patterns of metabolic effects have been seen following acute doses with paroxetine and fluoxetine, both of which are selective serotonin... 

Figure 2.17 The structural analogs talopram 58 and citalopram 59 (upper compounds), as well as nisoxetine 60 and fluoxetine 61 (lower compounds), are chemically closely related. Whereas 58 and 60 (left compounds) are highly selective norepinephrine uptake inhibitors (selectivity factors of 550 and 180, respectively), the close analogs 59 and 61 (right compounds) are selective serotonin uptake inhibitors (selectivity factors of 3400 and 54, respectively).

Talopram 58 and citalopram 59 (Figure 2.17) are closely related in their chemical structures. Nevertheless, talopram is a norepinephrine uptake blocker with a selectivity factor of about 550 against serotonin uptake, whereas citalopram is a serotonin uptake blocker, with a selectivity of 3400 against norepinephrine uptake. A similar selectivity difference applies to the even more closely related pair nisoxetine 60, with a norepinephrine uptake selectivity of about 180, and fluoxetine 61 (Figure 2.17), with a serotonin uptake selectivity of 54 [33],... 

The selective serotonin re-uptake inhibitors (SSRIs) that are currently available are fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, and escitalopram. They are widely marketed and are in many countries a major alternative to tricyclic antidepressants in the treatment of depression. The SSRIs are structurally diverse, but they are all inhibitors of serotonin uptake, with much less effect on noradrenaline. They have slight or no inhibitory effect on histaminergic, adrenergic, serotonergic, dopaminergic, and cholinergic receptors (1). 

Fluoxetine hydrochloride (Prozac, Fontex, etc. Figure 17.2) is an antidepressant of the SSRI class. As a structural analogue of serotonin, it competes for its re-uptake at the... 

Walsh SL, Preston KL, SuUivan JT, Fromme R, Bigelow GE (1994) Fluoxetine alters the effects of intravenous cocaine in humans. J Clin Psychopharmacol 14 396-407 Weyand S, Shimamura T, Yajima S, Suzuki S, Mirza O, Krusong K, Carpenter EP, Rutherford NG, Hadden JM, O Reilly J, Ma P, Saidijam M, Patching SG, Hope RJ, Norbertczak HT, Roach PC, Iwata S, Henderson PJ, Cameron AD (2008) Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter. Science 322 709-713... 

The antidepressant compound lubazodone (8) illustrates the breadth of the structural requirements for serotonin selective reuptake inhibitors the structure of this agent departs markedly from that of fluoxetine, the first drug in this class. The compound at hand also exemplifies the current trend for preparing drugs in chiral form. Thus reaction of the indanol (6) with the mesylate from chiral glycidic oxide in the presence of base leads to the epoxypropyl ether (7) with retention of chirality. Treatment intermediate 7 with aminoethylsulfonic acid closes the morpholine ring. Product 8 consists of pure (5) enantiomer. ... 

---