Imipramine structure

Most of the widely used antidepressants are tricyclics related to imipramine. A 1-phenyltetrahy-droisoquinoline analogue, nomifensine (60), departs from this structural pattern. Hiarmacologi-cally it inhibits the reuptake of catecholamines such as dopamine at neurons. It can be synthesized by alkylation of 2-nitrobenzyl-methylamine with phenacyl bromide followed by catalytic reduction of the nitro group (Pd-C) and then hydride reduction of the keto moiety to give 59. Strong acid treatment leads to cyclodehydration to nomifensine (60) [17]. 

The tricyclic antidepressants (TCAs) derive their name from their three-ringed molecular structure (Fig. 20.3) and emerged, in 1958, from a search for better neuroleptics than chlopromazine among the phenothiazines. The prototype, imipramine, turned out to be ineffective in treating the positive symptoms experienced by schizophrenics but it did relieve their depression (negative symptoms). In fact, imipramine is still the standard agent against which novel antidepressants are compared in clinical trials. 

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. 

Tricyclic Antidepressants (TCAs). Like iproniazid, the first TCA was also developed in the 1950s for another purpose. Imipramine (Tofranil) is structurally similar to the early antipsychotics and was hoped to provide an alternative to chlor-promazine (Thorazine). It proved to be a poor antipsychotic but was surprisingly found to be an effective antidepressant. The tricyclics are so named because a three-ringed structure forms the hub of the molecule. 

The true tricyclics are often subdivided into tertiary and secondary amine groups. Structurally, the difference lies in the length of side chains branching off the basic three-ringed hub of the molecule. Clinically, side effects are most common and most severe with the tertiary amine medications such as amitriptyline, imipramine, and doxepin. The secondary amines are generally better tolerated. It should be added that two of the tertiary amine TCAs, amitriptyline and imipramine, are metabolized... 

Clinically used local anesthetics are either esters or amides. This structural element is unimportant for efficacy even drugs containing a methylene bridge, such as chlorpromazine (p. 236) or imipramine (p. 230), would exert a local anesthetic effect with appropriate application. Ester-type local anesthetics are subject to inactivation by tissue es-Ltillmann, Color Atlas of Pharmacology... 

Desipramine Desipramine, 10,1 l-dihydro-5-[3-(methylamino)propyl]-5H-dibenz[b,f] azepine (7.1.13), differs from imipramine in that it contains only one methyl group on the nitrogen atom of the propylamine side chain. The suggested methods of desipramine synthesis are very simple, and the difference lies only in the manner in which the secondary methylamine group is introduced into the structure of the drug. 

This chapter describes the structure and neurochemical function of TCAs, metabolism and significant interactions with other medications, side effects, and specific recommendations for monitoring of side effects in children and adolescents. Because of the recent concern regarding the sudden deaths of children stabilized on TCAs, particular attention will be paid to the potential cardiovascular effects of these medications. The chapter will focus on the five TCA medications that have been most widely used in children amitriptyline (AMI), nortriptyline (NT), imipramine (IMI), desipratnine (DMI), and clomipramine (CMI). 

Shortly after iproniazid was shown to have antidepressant properties, imipramine was introduced as the first tricyclic antidepressant. These drugs received the name tricyclic because their structure contains three molecular rings. At first, imipramine was investigated as a possible treatment for the psychotic episodes associated with schizophrenia, a severe mental disorder that causes hallucinations and delusions, because it was chemically similar to another effective anti-schizophrenia drug. Imipramine did not reduce the severity of psychotic episodes, but it did elevate the mood of the patients who took it. In the late 1950s, it was released in the United States under the name Tofranil for the treatment of depression. 

Since that time, many other tricyclic antidepressants have been studied and put into use. They are all structurally related to imipramine. The active metabolite of imipramine is desipramine. This means that imipramine breaks down into desipramine in the body, and the resulting desipramine actually improves mood. Because their structures are so similar, scientists assume that they have a similar action in the body. 

It is structurally and chemically related to tricyclic antidepressant drug imipramine and pharmacologically it is similar to diphenyl hydantoin sodium. It is effective in grandmal and psychomotor epilepsy and also in the treatment of trigeminal neuralgia (a condition characterized by paroxysms of intense pain of stabbing nature within the area of distribution of trigeminal nerve without sensory loss). 

One common denominator of all antipsychotics is the biockade of centrai dopamine (DA) receptors. As a result, extrapyramidal reactions, particularly parkinsonian symptoms, are a major adverse effect of many of these drugs, as well as an important clue to their mechanism of action. True Parkinson s disease is caused by a DA deficiency in the nigrostriatal system. Further, crystallographic data have demonstrated that CPZ s molecular configuration is similar to that of DA, which could explain its ability to block this neurotransmitter s receptors. Drugs with similar structures that do not block DA receptors (e.g., promethazine, imipramine) do not have antipsychotic activity. Another example is the isomer of flupenthixol, which blocks DA receptors is an effective antipsychotic, but the isomer that does not is ineffective (7). The other family of dopamine receptors, D and Dg, have not yet been implicated in psychosis. 

Post and Kramlinger (386) have also suggested that lithium added to carbamazepine may be useful in treatment-resistant mood-disordered patients. One possible basis for this approach is that carbamazepine, which has a tricyclic ring structure similar to imipramine, may sensitize postsynaptic serotonin receptors in a similar way to standard drugs such as imipramine. A mood stabilizer (e.g., lithium, valproate, carbamazepine) plus antidepressant may benefit some rapid cycling or mixed bipolar patients, attenuating the propensity to switch from mania to depression. 

CBZ s molecular structure is similar to imipramine. It is primarily metabolized by the liver and, like lithium, has a narrow therapeutic index, predisposing to toxicity with elevated serum levels. 

SNRIs are chemically unrelated to each other. Venlafaxine was discovered in the process of evaluating chemicals that inhibit binding of imipramine. Venlafaxine s in vivo effects are similar to those of imipramine but with a more favorable adverse-effect profile. All SNRIs bind the serotonin (SERT) and norepinephrine (NET) transporters, as do the TCAs. However, unlike the TCAs, the SNRIs do not have much affinity for other receptors. Venlafaxine and desvenlafaxine are bicyclic compounds, whereas duloxetine is a three-ring structure unrelated to the TCAs. Milnacipran contains a cyclopropane ring and is provided as a racemic mixture. 

The Division of Drug Experience of the US Department of Health and Welfare issued a note on five cases of the syndrome of inappropriate antidiuretic hormone secretion and drugs to which it has been attributed (1137). All involved drugs with a tricyclic structure one patient was taking imipramine, three carbamazepine, and the others the closely related muscle relaxant cyclobenz-aprine. The dosage of imipramine was 50 mg/day for 3 weeks and the patient was a 72-year-old woman. Other cases have been reported, involving amitriptyline (1137), imipramine, and protriptyline (SEDA-17,17). 

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-). 

Substrates for this enzyme include (R)-mephobarbital, moclobemide, proguanil, diazepam, omeprazole, and imipramine, which do not show obvious structural or... 

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