Tricyclic antidepressants structure

In the non-tricyclic antidepressant structures there are promising drugs in which the side effects of the tricyclics are absent Table 6.2). How far other serious side effects will limit their use will be disclosed by future studies, but surely some compounds will survive the careful clinical examinations. 

NON-TRICYCLIC ANTIDEPRESSANT STRUCTURES CARBOXYLIC ACIDS, ESTERS, AMIDES AND AMIDOXIMES An alanine ester, alaproclate (7) and some of its analogues selectively inhibit 5-... 

The very slow onset of action and side effects which follow from the anticholinergic side effects characteristic of the tricyclic antidepressants has led to a continuing effort to find replacements from other structural classes which might thus be devoid of this defect. A series of alkoxy phenylpropylamines has been investigated extensively in this search for non-tricyclic antidepressants. The most recent analogue, tomoxetine (69), is accessible by the same route [15] used to prepare the earlier analogue, nisoxetine, in which methoxyl replaces the ortho methyl group. 

Cocaine and desipramine inhibit the reuptake of monoamine neurotransmitters whereas amphetamine, which is a phenylalkylamine - similar in structure to the catecholamines, see Fig. 4 - competes for uptake and more importantly, evokes efflux of the monoamine neurotransmitters. All of them exert antidepressant effects. Cocaine and amphetamine are addictive whereas tricyclic antidepressants and their modern successors are not. The corollaty of the addictive properties is interference with DAT activity. Blockade of DAT by cocaine or efflux elicited by amphetamine produces a psychostimulant effect despite the different mechanisms even the experienced individual can hardly discern their actions. Because of the risk associated with inhibiting DAT mediated dopamine clearance the antidepressant effects of psychostimulants has not been exploited. 

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. 

Figure 20.3 The basic structure of tricyclic antidepressants with some well-known examples...

Benzyhydrol Derivatives Cyprolidol (26), a highly modified benzhydrol derivative, is reported to exhibit antidepressant activity it is of note that this agent bears little structural relation to either the MAO inhibitors or tricyclic antidepressants. Addition of the carbene from... 

Tricyclic antidepressant A family of first-generation (typical) antidepressants with a three-ringed structure that inhibit the action of monoamine transporters. 

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. 

In accordance with the structure of the BBB as a double Upid bilayer, classical neuroactive drugs such as benzodiazepines, neuroleptics and tricyclic antidepressive agents, are all small lipophilic molecules. These small molecular weight neuropharmaceuticals were selected by a trial and error approach because their structural characteristics allow for diffusion-mediated,... 

Substrates for CYP2D6 include tricyclic antidepressants, p-blockers, class 1 anti-arrhythmics. In brief, the structural similarities of many of the substrates and inhibitors in terms of position of hydroxylation, overall structure (aryl-alkylamine) and physicochemistry (ionized nitrogen at physiological pH), have allowed template models such as that illustrated as Figure 7.3 to be constructed. 

Iprindol (25) is yet another antidepressant drug that differs structurally from the classical tricyclic antidepressants. Condensation of phenylhydrazine and cyclooctanone by the Rogers-Corson modification of the Fischer indole synthesis affords the tricyclic intermediate, 24. The active hydrogen of 6,7,8,9,10-hexahydro-5H-cyclooct[b]indole (24) is removed by reaction with sodium metal in DMF and the resulting salt condensed with 3-dimethylaminopropyl chloride. There is thus obtained iprindol (25). ... 

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. 

Cyclobenzaprine is structurally similar to tricyclic antidepressants. It acts at the brain stem level. It is used as an adjuvant agent for relieving muscle spasms associated with severe diseased conditions of the muscle. A synonym of this drug is flexeril. 

Pharmacology The tricyclic antidepressants (TCAs), structurally related to the phenothiazine antipsychotic agents, possess 3 major pharmacologic actions in varying degrees Blocking of the amine pump, sedation, and peripheral and central... 

Pharmacology Cyclobenzaprine, structurally related to the tricyclic antidepressants (TCAs), relieves skeletal muscle spasm of local origin without interfering with muscle function. It is ineffective in muscle spasm caused by CNS disease. The net effect is a reduction of tonic somatic motor activity, influencing both gamma and alpha motor systems. 

Carbamazepine is a tricyclic iminostilbene derivative and structurally related to the tricyclic antidepressants. It is used as a first-line agent for the management of generalized tonic-clonic epilepsy. It is also highly effective for partial seizures but has no efficacy in patients with absence seizures or atonic seizures. In epilepsy it supposedly has the same mechanism of action as phenytoin. An other well... 

Geriatric Considerations - Summary Cyclobenzaprine is a skeletal muscle relaxant which is structurally related to the tricyclic antidepressants with anticholinergicprop-erties and it is very sedating. It is used for acute muscle pain and should not be used chronically. Its usefulness in the older adult is limited by its potential to cause adverse effects. 

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. 

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