Antidepressants structure-activity relation

R. A. Maxwell, H. L. White (1978). Tricyclic and monoamine oxidase inhitor antidepressants structure-activity relations. In L. L. Iversen, S. D. Iversen, S. H. Snyder (Eds.). Handbook of Psychopharmacology, vol. 14. New York Plenum Press, pp. 83-155. 

In the present review of recent developments in those so-called non-tricyclic antidepressants , the test methods on which the conclusion of probably therapeutically active is based are evaluated. Then the activities of the various new structures, classified by structural resemblance, are discussed. Finally an attempt is made to derive some general structure-activity relations (SAR) and to draw some final conclusions about the whole subject. An index of compound names has been added as an aid to finding information about individual compounds and comparing the phases of development of these. 

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],... 

Nefazodone is a phenylpiperazine antidepressant, structurally related to trazodone, but it has less alphai-adreno-ceptor antagonist activity and is therefore less sedative. It is a potent 5-HT2 receptor antagonist at postsynaptic receptors, and a weak serotonin reuptake inhibitor. In trials it was more effective than placebo and comparable to imipramine. 

Remarkably little has been published on the structure-activity relationships of reuptake inhibitors. Close inspection of these inhibitors reveals that many of them are related in structure to ring-opened tricyclic antidepressants. Indeed, small structural changes can result in shifts in selectivity. For example, fluoxetine (9)is a serotonin-selective reuptake inhibitor, whereas nisoxetine (49) is a norepinephrine-selective reuptake inhibitor. 

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... 

Pridefine (80) is a somewhat structurally related antidepressant. It is a centrally active neurotransmitter blocking agent. It blocks norepinephrine in the hypothalamus but does not affect dopamine or 5-hydroxytryptamine. Its synthesis be-(jins by lithium amide-promoted condensation of diethyl succinate and benzophenone followed by saponification to 78. Heating in the presence of ethylamine gives N-ethylsuccinimide 79. Lithium aluminum hydride reduction completes the synthesis of pridefine (80)... 

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. 

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. 

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. 

An important group of antihistamines, the pheniramines (92), use 2-chloropyridine as a basic feedstock. The activity of chlorpheniramine (92 X = Cl) as an H receptor blocker has recently been reported (79MI20906). Zimelidine (93), a relatively new compound of related structure, exhibits antidepressant activity with reduced subjective side-effects found with other antidepressants (79MI20907). 2-Halopyridines also function as precursors to another group of antihistamines exemplified by p-bromotripelennamine (94) (51USP2572569). 

Methylphenidate is a piperidine derivative, structurally related to amphetamine, but a milder central nervous system stimulant. However, large doses produce symptoms of generalized central nervous system stimulation and convulsions. It is more active than amphetamine as an antidepressant, as a treatment for overdosage of depressant drugs, and in exacerbating schizophremc symptoms. Occasionally, anorexia, nausea, dry mouth, nervousness, insomnia, dizziness, and palpitation have been recorded. 

Amoxapine. Consideration of the structure of amoxap-inc. 2-chloro-ll-(l-pipcra/inyl)dibcn/.- b./] l,4 oxuzepinc (Asendin). reinforces the fact that many antidepressants are very closely related to antipsychoties. Indeed,. some, including amoxapine. have significant effects at D. receptors. The Ai-methyl-substituted relative of amoxapine is the antipsychotic loxapine (Loxitane). The H-hydroxy metabolite of amoxapine is reportedly active as an antidepre.ssant and us a Dj receptor blocker. 

The MAO inhibitor tranylcypromine is amphetamine-like in structure but interacts only weakly at DA transporters. The phenylpiperazine nefazodone, and to a lesser extent, the structurally related trazodone have weak inhibitory actions on 5-HT transport nefazodone also may have a minor effect on NE transport. This agent also has a prominent direct antagonistic effect at S-HT receptors that may contribute to antidepressant and anxiolytic activity. Both drugs also may inhibit presynaptic 5-HTj subtype autoreceptors to enhance neuronal release of 5-HT, though they probably also exert at least partial-agonist effects on postsynaptic 5-HTj receptors. Trazodone also blocks cerebral and Hj receptors, possibly contributing to its tendency to induce priapism and sedation, respectively. 

Another strategy is to directly enhance dopamine function as well as the activities of B-cell lymphoma protein 2 (Bcl-2), which is another important component that may play a role, eventually, in the resolution of depression. Examples of various non-selective enhancers of dopamine that also stimulate Bcl-2 are pergolide, ropinirole, and selegiline, while pramipexole may directly enhance Bcl-2. The antidepressant effect exhibited by enhanced dopaminergic transmission is thought to be at least partially related to increased dopaminergic transmission in limbic structures (e.g. the nucleus accumbens). - ... 

Cyclobenzaprine is a central-acting muscle relaxant that is commonly used to treat pain from injury, muscle spasms, and other painful musculoskeletal conditions. It is structurally related to first-generation tricyclic antidepressants such as imipramine and amitriptyline and appears to inhibit the uptake of norepinephrine in the locus coeruleus. Tricyclic compounds with norepinephrine reuptake-inhibiting properties have been shown to exert analgesic effects in chronic nerve and muscle pain by acting primarily within the central nervous system at brainstem as opposed to spinal cord levels, although their action on the latter may contribute to their overall skeletal muscle relaxant activity. The exact mechanism of action of cyclobenzaprine is unknown. 

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