Amitriptyline

Amitriptyline hydrochloride and imipramine hydrochloride are similar in structure, with the exception of the nitrogen in the center ring, and belong to the family of phenothiazine compounds. Finally, the two-carbon bridge linking the aromatic rings may be ethyl (-CH2CH2-) or ethylene (-CH=CH-). 

These compounds are central nervous system stimulants or antidepressants although such activity is usually restricted to compounds having a two- or three-carbon side chain and methyl-substituted or unsubstituted amino groups in the side chain although derivatives with substituents on the aromatic ring may have pharmacological activity. 

The synthesis of amitriptyline starts from the key intermediate dibenzo-suberone (manufactured from phthalic anhydride) and can proceed by two pathways (Fig. 1). Treatment of dibenzosuberone with cyclopropyl Grignard gives the tertiary alcohol after hydrolysis. Reaction of the alco- 

Amitriptyline is recommended for the treatment of mental depression, with improvement in mood seen in 2 to 3 weeks after the start of medication. 

Sample preparation 1 mL Serum + 500 p,L 750 mM pH 10 sodium bicarbonate/carbonate buffer -I- 50 jxL IS in EtOH water 50 50 + 8 mL heptane isoamyl alcohol 98 2, shake at 250 cycles/min for 5 min, centrifuge at 1500 g for 10 min, freeze in dry ice/EtOH. Remove the organic layer and add it to 150 p,L 22 mM pH 2.5 KH2P04/phosphoric acid buffer, shake at 250 cycles/min for 5 min, centrifuge at 1500 g for 10 min, freeze in dry ice/EtOH. Discard the organic layer, inject a 65 p,L ahquot of the aqueous layer. 

Mobile phase MeCN buffer 45 55 (Buffer was 44 mM KH2PO4 containing 1.5 mlVL trie-thylamine, adjusted to pH 2.5 with phosphoric acid.) 

Internal standard l-(3-(dimethylamino)propyl)-l-(p-chlorophenyl)-l,3-dihydroisobenzo-furan-5-carbonitrile (LU 10-202) (Lundbeck, Copenhagen) (8.33) 

Simultaneous chlorprothixene, clomipramine, clozapine, dupenthixol, haloperidol, levo-mepromazine, perphenazine, zuclopenthixol 

Olesen, O.V. Linnet, K. Simplified high-performance liquid chromatographic method for the determination of citalopram and desmethylcitalopram in serum without interference from commonly used psychotropic drugs and their metabolites. J.Chromatogr.B, 1996, 675, 83-88 

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Eerguson, G. K. Quantitative HPLG Analysis of a Psychotherapeutic Medication Simultaneous Determination of Amitriptyline Hydrochloride and Perphenazine, /. Chem. Educ. 1998, 75, 1615-1618. 

Trigclic Antidepressants. Imipramine (38) was introduced in the late 1950s as one of the first pharmacotherapies for depression. At that time, chlorproma2ine [50-53-3] was the first effective antipsychotic treatment to be discovered. Researchers looked for similar chemical stmctures and imipramine was found to be effective in the symptomatic treatment of depression. Over the years, other congeners, such as desipramine (39), amitriptyline (40), and dothiepin (41), were synthesized and shown to be clinically efficacious antidepressant dmgs (121). These substances, known under the general mbric of tricycHc antidepressants, share a basic chemical stmcture comprising... 

Doxepin [1668-19-5] (38), unlike other commercially available tricyclics, has an oxygen atom in the bridge between the two aromatic rings. It is marketed as a cis—trans mixture (1 5) of isomers, both of which are active. This close relative of amitriptyline (33) has both sedative and anxiolytic properties associated with its antidepressant profile. Maprotiline [10262-69-8] (39) and amoxapine [14028-44-5] (40) are pharmacologically, although not chemically, similar to the tricycHc secondary amines. Clomipramine [303-49-1] (41) has similar pharmacological and antidepressant efficacy. However, clomipramine is approved by the U.S. FDA only for the treatment of obsessive—compulsive disorder. Representative brands of tricycHc antidepressants marketed in the United States are Hsted in Table 2. 

Two recently introduced antidepressants are notable m that they are selective serotonin uptake inhibitors Citalopram (19) is reported to be as effective as amitriptyline m the treatment of endogenous depression [75, 16] Fluoxetine (20) as the hydrochlonde is approved for major depressive disorders mcludmg those with concomitant anxiety Interestmgly, it also appears useful m the treatment of obesity [17]... 

Dibenzo[a,dlcyclohepta-1,4-diene-5-one Amitriptylin oxide Dibenzo[a,el cycloheptatrien-5-one Cyproheptadine 5H-Dibenzo (a,d 1 cycloheptene Protriptyline... 

Amitriptylin oxide 3-(Dimethylamino) propyl chloride Amitriptyline HCI Ch/orprothixene Clomipramine Cyclobenzaprine Imipramine HCI Oxetorone fumarate Prothipendyl HCI... 

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