Iprindole

The adverse side-effects of the TCAs, coupled with their toxicity in overdose, provoked a search for compounds which retained their monoamine uptake blocking activity but which lacked the side-effects arising from interactions with Hj, aj-adreno-ceptors and muscarinic receptors. One of the first compounds to emerge from this effort was iprindole, which has an indole nucleus (Fig. 20.3). This turned out to be an interesting compound because it has no apparent effects on monoamine uptake and is not a MAO inhibitor. This, together with its relatively minor antimuscarinic effects, led to it commonly being described as an atypical antidepressant. Mechanisms that could underlie its therapeutic actions have still not been identified but, in any case, this drug has now been withdrawn in the UK. 

Rotzinger, S, Bourin, M, Akimoto, Y, Coutts, RT and Baker, GB (1999) Metabolism of some second and fourth generation antidepressants iprindole, viloxazine, buproprion, mianserin, maprotiline, trazodone, nefazodone and venlafaxine. Cell. Molec. Neurobiol. 19 427 42. 

Fuller, R.W., and Hemrick-Luecke, S.K. Further studies on the long-term depletion of striatal dopamine in iprindole-treated rats by amphetamine. Neuropharmacology 21 433-438, 1982. 

Ricaurte, G.A. Guillery, R.W. Seiden, L.S. and Schuster, C.R. Nerve terminal generation after a single injection of dopamine depletion. Brain Res 291 378-382, 1984. 

Aspeslet LJ, Baker GB, Coutts RT, Torok-Both GA. 1994. The effects of desipramine and iprindole on levels of enantiomers of fluoxetine in rat brain and urine. Ghirality 6 86. 

The series of compounds from which iprindole was selected has been described [185], further pharmacological details (particularly of iprindole) being conveyed [186-8] as contributory to the development of a new theory of brain function (in the context of stimulation and depression) involving novel methods of drug evaluation. 

Chemically, iprindole (XVI, Prondol, Wy-3263, originally called pramindole) like oxypertine, is an indole derivative. 

Iprindole has received close clinical scrutiny. It has been compared with a placebo [190, 191] with imipramine [192-195] and with both [196]. 

All were double-blind controlled evaluations and established iprindole as at least as effective as imipramine, and one study [195] included an examination of the doctor-patient interaction as a factor in such work (a similar discussion was felt necessary, as noted above [179] in the evaluation of oxpertine). In only two [192, 194] of the above reports is it possible to estimate the frequency and severity of anticholinergic side effects, thou in the one case [192] the care taken in the experimental design and the number of patients observed leaves little doubt that the dry mouth, constipation, etc. characteristic of imipramine therapy is either greatly reduced or even absent during iprindole treatment. This point is confirmed in an extension of this team s work to include a 12 month toxicity study [197] which, in addition, failed to produce evidence of haemopoitic, hepatic, cardiac, ocular or renal damage. Similar results followed other work. 

It would appear, from the above, that the novel tricyclic system of iprindole has conferred properties which promise more patient comfort, and therefore more cooperation, in the treatment of depressive illness. 

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). ... 

Indomethacin, 318 Insulin, in diabetes, 136 lodination of phenols, 97, 314 lodothiouracyl, 265 Iprindol, 318 Iproniazid, 254 Isoaminile, 82 Isobucaine, 12 Isocarboxazine, 233... 

Baxter BL, Gluckman MI Iprindole an antidepressant which does not block REM sleep. Nature 223 750-752, 1969... 

Iprindole 6,5,8 ring structure Weak action on amino pump mechanism... 

Iprindole is a 6,5,8 tricyclic compound, whose first two rings form an indole nucleus (SED-7, 27). It is of some theoretical interest, in that it is weak in its action on the amine pump mechanism. Adverse effects are reported as being similar to those of other tricyclic antidepressants (1,2). 

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