Clomipramine (Anafranil) is up to 50 times as potent as imipramine in some bioassays. This does not imply clinical superiority, but it might be informative about tricyclic and, possibly, other reuptake inhibitors. The chloro replacing the H-substituent could increase potency by increasing distribution to the CNS, but it is unlikely that this would give the potency magnitude seen. It might be conjectured that an H-bond between the protonated amino group (as in vivo) and the unshared electrons of the chloro substituent might stabilize a jS-arylamine-like shape and give more efficient competition for the transporter. The drug is an antidepressant. It is used in obsessive-compulsive disorder, an anxiety disorder that may have an element of depression.
Amitriptyline, 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohep-ten-5-ylidene)-N,N-dimethyl-1 -propanamine hydrochloride, 5-(3-dimethylaminopropylidene)-10,11-dihydro-5H -dibenzo[a,d]cycloheptene hydrochloride (Elavil), is one of the most anticholinergic and sedative of the TCAs. Because it lacks the ring-electron-enriching nitrogen atom of imipramine, metabolic inactivation mainly proceeds not at the analogous 2-position but at the benzylic 10-position (i.e., toluene-like metabolism predominates). Because of the 5-exocyclic double bond, E- and Z-hydroxy isomers are produced by oxidation metabolism. Conjugation produces ex-cretable metabolites. As is typical of the dimethyl compounds, N-demethylation occurs, and nortriptyline is produced, which has a less anticholinergic, less sedative, and more stimulant action than amitriptyline. Nortriptyline is a SNERI31; the composite action of drug and metabolite is nonselective.
Pertinent biological and chemical properties for nortriptyline, 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)N-methyl-1-propanamine hydrochloride, 5-(3-methyl-amino-propylidene)-10,11-hydro-5H-dibenzo[a,d] cycloheptene hydrochloride (Aventyl, Pamelor), are given previously in the discussion of amitriptyline. Metabolic inactivation and elimination are like those of amitriptyline. Nortriptyline is a selective NE transporter (NET) inhibitor.31
Protriptyline hydrochloride, N-methyl-5H-dibenzo[a,d]-cycloheptene-5-propylamine hydrochloride, 5-(3-methyl-aminopropyl)-5H-dibenzo[a,d]cycloheptene hydrochloride (Vivactil), like the other compounds under consideration, is an effective antidepressant. The basis for its chemical naming can be seen by consulting the naming and the structure of imipramine. Protriptyline is a structural isomer of nortriptyline. Inactivation can be expected to involve the relatively localized double bond. Because it is a monomethyl compound, its sedative potential is low.
For details of chemical nomenclature, consult the description of imipramine. Replacement of hydrogen with an œ-methyl substituent produces a chiral carbon, and trimipramine (Surmontil) is used as the racemic mixture. Biological properties reportedly resemble those of imipramine.
Doxepin, 3-dibenz[b,e]-oxepin-11(6H)ylidine-N,N-dimethyl-1-propanamine hydrochloride, N,N-dimethyl-3-(dibenz[b,e] oxepin-11(6H)-ylidene)propylamine (Sinequan, Adapin), is an oxa congener of amitriptyline, as can be seen from its structure.
The oxygen is interestingly placed and should influence oxidative metabolism as well as postsynaptic and presynaptic binding affinities. The (Z )-isomer is the more active, although the drug is marketed as the mixture of isomers. The drug overall is a NE and 5-HT reuptake blocker with significant anticholinergic and sedative properties. It can be anticipated that the nor- or des- metabolite will contribute to the overall activity pattern.
Maprotiline hydrochloride, N-methyl-9,10-ethanoanthracene-9(10#)-propanamine hydrochloride (Ludiomil), is sometimes described as a tetracyclic rather than a tricyclic antidepressant. The description is chemically accurate, but the compound, nonetheless, conforms to the overall TCA pharmacophore. It is a dibenzobicyclooctadiene and can be viewed as a TCA with an ethylene-bridged central ring. The compound is not strongly anticholinergic and has stimulant properties. It can have effects on the cardiovascular system. It is a SNERI.31
Consideration of the structure of amoxapine, 2-chloro-11-(1-piperazinyl)dibenz-[£,/] [1,4]oxazepine (Asendin), reinforces the fact that many antidepressants are very closely related to antipsychotics. Indeed, some, including amoxapine, have significant effects at D2 receptors. The n-methyl-substituted relative of amoxapine is the antipsychotic loxapine (Loxitane). The 8-hydroxy metabolite of amoxapine is reportedly active as an antidepressant and as a D2 receptor blocker.
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