Antidepressant agents

Future Outlook for Antidepressants. Third-generation antidepressants are expected to combine superior efficacy and improved safety, but are unlikely to reduce the onset of therapeutic action in depressed patients (179). Many dmgs in clinical development as antidepressive agents focus on estabhshed properties such as inhibition of serotonin, dopamine, and/or noradrenaline reuptake, agonistic or antagonistic action at various serotonin receptor subtypes, presynaptic tt2-adrenoceptor antagonism, or specific monoamine—oxidase type A inhibition. Examples include buspirone (3) (only... 

Hydrazides of isonicotinic acid have been used as antidepressant agents by virtue of their monoamine oxidase-inhibiting activity the pyridine ring has been shown to be replaceable by an... 

As noted earlier, most classical antidepressant agents consist of propylamine derivatives of tricyclic aromatic compounds. The antidepressant molecule tametraline is thus... 

A rather simple derivative of imidazoimidazoline has been described as an antidepressant agent. Preparation of this compound starts with the displacement of the nitramine grouping in imidazoline derivative by phenyl ethanol amine The product of this reaction is then treated with thio-nyl chloride. The probable chloro intermediate ( ) cyclizes under the reaction conditions to afford imafen (5. ... 

Antidepressant agents show almost the same degree of tolerance as to the nature of the tricyclic moiety as do the antipsychotic agents. Thus the dehydration product(s) from the condensation of ketone 9 with the Grignard reagent from 3-chloroethyl-N, J -dimethylamine affords the antidepressant diothiepin (98). ... 

Historically, both the tricyclic antipsychotic and antidepressant agents are derived in almost direct line from a series of tricyclic antihistaminic compounds (see 104 below). Minor changes in structure in some of the newer... 

A remarkably simple fused indole devoid of the traditional side chains is described as an antidepressant agent. Michael addition of the anion from indole ester 119 to acrylonitrile affords the cyanide 120. Selective... 

Yet another nontricyclic antidepressant consists of a relatively simple morpholine derivative. Acylation of aziridine with p-chlorobenzoyl chloride gives the amide 130. This intermediate is. sufficiently reactive to undergo ring opening on treatment with morpholine. The product is the antidepressant agent moclobemide (131) 33J. 

Azaloxan (12) is an antidepressant agent. Its synthesis can be accomplished starting with the reaction of catechol (7) and 3,4-dibromobutyronitrile (obtained by addition of bromine to the olefin) to give l,4-benzodioxan-2-ylacetonitrile (8). A series of functional group transformations ensues [hydrolysis to the acid (9), reduction to the alcohol (10) and conversion to a tosylate (11)] culminating in an SN-2 displacement reaction on tosylate 11 with l-(4-piperidinyl)-2-imidazolidi-none to give azaloxan (12) [3]. 

Antidepressive agents which increase synaptic availability of serotonin and noradrenaline have been empirically found to be efficacious against chronic pain, particularly that of neuropathic origin. 

The continuing development of antidepressant agents has increased the availability of newer dmgs that have similar efficacy but are more expensive than the older antidepressants (Song et al, 1993). This chapter addresses the complex question of whether there is clear evidence that the use of any single antidepressant or group of antidepressants is more cost-effective than any other. 

Attempts to find the cause(s) of depression have adopted two main approaches. One is to look for the neurobiological basis of depression in human subjects and animal models of this condition. The second is to investigate the pharmacology of established antidepressant agents to see whether they consistently augment some, and ideally the same, neurobiological targets in the brain. 

The use of animal models for depression has two main objectives. One is to provide a behavioural model that can be used to screen potential antidepressant treatments. For this, the behaviour does not have to be an animal analogue of depression all that is needed is for it to be consistently prevented by established antidepressant agents (i.e. no false negatives) but not by drugs which have no antidepressant effect in humans (i.e. no false positives). 

The relative incidence of adverse effects among some of the newer antidepressant agents are shown in Table 35-4.9,13,28... 

DeVane, C. L. (1994). Pharmacogenetics and drug metabolism of newer antidepressant agents. /. Clin. Psychiatry, 55(38-45) 46-7. 

Escobar, J. I. Tuason, V. B. (1980). Antidepressant agents-a cross-cultural study. Psychophar-macol. Bull., 16,49-52. 

Which of the following is an antidepressant agent that selectively inhibits serotonin (5-HT) uptake with minimal effect on norepinephrine uptake ... 

Polysomnographic sleep research has demonstrated that besides disturbances of sleep continuity in depression, sleep disturbance is also characterized by a reduction of slow-wave sleep and a disinhibition of REM sleep, with a shortening of REM latency, a prolongation of the first REM period, and increased REM density [62]. Most effective antidepressant agents suppress REM sleep, and depressive symptoms are at least transiently alleviated by manipulations of the sleep-wake cycle, such as sleep deprivation or a phase advance of the sleep period [63]. Thus, there appears to be a bidirectional relationship between sleep, sleep alterations and mood. 

Recently, compound CM 30366 (CAS 82239-52-9), the 4-hydroxyphenyl analogue of minaprine, also has been studied in some detail. Based on the results obtained in a behavioural study in mice and rats, it has been concluded that CM 30366 may be of potential therapeutic usefulness due to a significant atypical dopamine-like activity [159], Also thiophene isosters of minaprine have been claimed as antidepressant agents [131],... 

Compound SR 95191 (42, CAS 94011-82-2) is another aminopyridazine-derived antidepressant agent structurally closely related to minaprine, which has been investigated in France quite recently [ 160-162], This compound has been shown to be active in most animal models of depression with an activity profile resembling that of a selective type A MAO inhibitor [ 160], Recently, it has been found that this inhibition is selective, reversible and competitive in vivo in vitro, however, SR 95191 behaves like an irreversible MAO-A inhibitor [162],... 

Wienkers, L.C., Allievi, C., Hauer, M.J. and Wynalda, M.A. (1999) Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes. Drug Metabolism and Disposition, 27 (11), 1334-1340. 

The variety of antidepressant agents developed all seem to share one commonality alteration of monoamine systems (Bolden-Watson and Richelson 1993 Bonhomme and Esposito 1998). Only very recently have drugs that work outside of monoamine systems been shown to have reliable antidepressant effects. 

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