Antidepressant activity

Potential antidepressant activity of lusaperidone (14) and its derivatives were investigated on al, q 2A, q 2B and q 2C receptor binding tests (00BMCL71). Hydrophilic controlled release formulations of 14 were developed and patented (00MIP8). 

Introduction of an additional double bond into the tricyclic nucleus, on the other hand, is consistent with antidepressant activity. Alkylation of the potassium salt, obtained on treatment of hydrocarbon, 38, with ammonia, with the chlorocarbamate, 39, affords the intermediate, 40. Basic hydrolysis leads to protrip-tylene (41). ... 

Two closely related indoles fused to an additional saturated ring have been described as CNS agents. The first of these is obtained in straightforward manner by Fischer indole condensation of functionalized cyclohexanone 0 with phenyl hydrazine (19). The product, cyclindole (21) shows antidepressant activity. The fluorinated analogue flucindole (26) can be prepared by the same scheme. An alternate route starting from a somewhat more readily available intermediate involves as the first step Fischer condensation of substituted phenyl hydrazine with 4-hydroxycyclohexanone (23). The resulting alcohol (24) is then converted to its tosylate (25). Displacement by means of dimethyl amine leads to the antipsychotic agent flucindole (26). ... 

Napamezole (68) is a dihydroimidazole derivative with antidepressant activity probably as a result of its combined a 2 adrenergic receptor blockuig and serotonin uptake blocking proper ties It can be synthesized by Wittig olefination of p-tetralone (65) with diethyl (cyanomethyl) phosphonate (66) and base to give nitnle 67 Imidazoline construction on the latter was smoothly... 

Antidepressant activity is retained when the two carbon bridge in imipramine is replaced by a larger, more complex, function. Nucleophilic aromatic substitution on chloropyridine 31 by means of p-aminobenzophenone (32) gives the bicyclic intermediate 33. Reduction of the nitro group (34), followed by intramolecular Schiff base formation gives the required heterocyclic ring system 35. Alkylation of the anion from 35 with l-dimethylamino-3-chloropropane leads to tampramine 36 [8]. 

The discovery that MAO has two isoenzymes with different distributions, substrate specificity and inhibitor sensitivity has helped to rehabilitate the MAOIs to some extent. These isoenzymes are the products of different genes on the X-chromosome and share about 70% sequence homology. Whereas noradrenaline and 5-HT are metabolised preferentially by MAOa, tyramine and dopamine can be metabolised by either isoenzyme. Selective inhibitors of MAOa (e-g- moclobemide Da Prada et al. 1989) should therefore be safe and effective antidepressants whereas the selective MAOb inhibitor, selegiline, should not have any appreciable antidepressant activity (Table 20.5). 

One might also speculate that PCA would have an effect similar to MDMA. Indeed, the early clinical data for PCA suggested that it possessed antidepressant activity (Verster and Van Praag 1970). This would suggest that the human psychopharmacology of PCA may well be closer to that of MDMA than fenfluramine, but it is unlikely that clinical studies can be carried out to study this. 

While such models of depression are quite useful in conceptualizing the mechanisms behind antidepressant activity, they are assuredly an oversimplification of the actual pathophysiologic process of the disorder. Depression probably involves a complex dysregulation of monoamine systems, and these systems, in turn, modulate and are modulated by other neurobio-logic systems. Thus, the underlying cause of depression may well extend beyond dysfunction of the monoamine system.10... 

Zanardi, R., Serretti, A. etal. (2001). Factors affecting fluvoxamine antidepressant activity influence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biol. Psychiatry, 50(5), 323-30. 

Cusin, C., Serretti, A., Zanardi, R. etal. (2002). Influence of monoamine oxidase A and serotonin receptor 2A polymorphisms in SSRI antidepressant activity. Int.. Neuropsychopharmacol, 5, 27-35. 

Serretti, A., Lorenzi, C., Cusin, C. et al. (2003). SSRIs antidepressants activity is influenced by Gbeta3 variants. Eur. Neuropsychopharmacol., 13, 117-22. 

Russo-Neustadt, A. A. Chen, M. J. (2005). Brain-derived neurotrophic factor and antidepressant activity. Curr. Pharm. Des., 11, 1495-510. 

Malcolm MacCoss, Christopher J. Swain, Timothy Harrison, Raymond G. Hill, Franz Hefti, Edward M. Scolnick, Margaret A. Casderi, Gary G. Chicchi, Sharon Sadowski, Angela R. Williams, Louise Hewson, David Smith, Emma J. Carlson, Richard J. Hargreaves and Nadia M. J. Rupniak, Distinct Mechanism for Antidepressant Activity by Blockade of Central Substance P Receptors , Science 281 (1998) 1640-45 Kuhn, Roland, Artistic Imagination and the Discovery of Antidepressants , Journal of Psychopharmacology 4, no. 3 (1990) 127-30... 

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... 

Anthracenes are planar by virtue of the necessity of maintaining aromaticity. When the central ring is reduced, an overall "butterfly" conformation is achieved. For reasons that are not yet understood at the molecular level, this conformation is often associated with central antidepressant activity. 

DIBENZOCYCLOHEPTANES AND DIBENZOCYCLOHEPTENES Drugs in this structural class have effected a revolution in the treatment of severely depressed patients such that deinstitutionalization is a feasible public policy. The compounds often show other CNS activities which depend on the length of the side chain. One-carbon chains generally lead to anticonvulsant activity amines separated from the nucleus by three carbons usually donvey antidepressant activity. Selected examples possess significant anticholinergic activity. 

Inclusion of an acetylenic linkage as part of the side chain is apparently consistent with antidepressant activity. Reaction of propargyl magnesium bromide with dibenzocycloheptadieneone leads to carbinol 82. A Mannich reaction with formaldehyde and dimethylamine leads to 83 which, upon dehydration... 

Interposition of an oxygen atom between the aromatic ring and the imidazoline-bearing side chain leads to a compound reported to show antidepressant activity. Its preparation begins with alkylation of phenol 125 with chloroacetonitrile to afford intermediate 126. Condensation of that nitrile with the... 

Although geneologically related to indoles, the dihydroindoles behave chemically rather like alkyl anilines. When diphenylamine reacts with chloro-propionyl chloride, amide 40 results this in turn readily cyclizes to oxindole 41. Sodium hydride followed by 2-chloroethyldimethylamine alkylates the 3-position (possibly through an intermediate aziridinium ion) partial demethylation is accomplished by refluxing with ethylchiorocarbonate, followed by hydrolysis of the intermediate carbamate to give indolinone 42, the antidepressant amedalin Repetition of this sequence on the chloropropyl homologue, followed by reduction of the appropriate indolinone produces dihydroindole 43, daledalin, which also has antidepressant activity. ... 

A related and relatively simple quinoline derivative has been reported to exhibit antidepressant activity. Its preparation merely involves displacement of halogen in 12 with piperazine to afford quipazine (13).6... 

Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 1998 281 1640-1645. 

Their beneficial effects in migraine prophylaxis are independent of antidepressant activity and may be related to downregulation of central 5HT2 and adrenergic receptors. 

Both enantiomers and the racemate of l-(3,4-dichlorophenyl)-3-azabicyclo [3.1.0]hexane, 27a-c, have been reported to be in development. The racemate, DOV 216,303, inhibits the reuptake of NE, 5-HT and DA with IC50 values of 20, 14 and 78 nM, respectively [85]. DOV 216,303 is active in tests predictive of antidepressant activity, including the mouse FST (minimum effective dose = lOmg/kg), reversal of tetrabenazine-induced ptosis and locomotor depression. DOV 216,303 was also reported to be well tolerated in phase I clinical trials [85,86], In a phase II study designed to explore safety and tolerability in depressed individuals, patients received either DOV 216,303 (50 mg, b.i.d.) or citalopram (20 mg, b.i.d.) for two weeks [85]. It was found that the side effect profile was not remarkably different between the two treatment groups. In addition, time-dependent reductions in Hamilton Depression Scores (HAM-D) were similar for both groups. 

The patent literature covers various types of pyridazine derivatives for which antidepressant activity has been claimed. 

Compounds which are of interest in this context include 4-oxadiazolylpyrid-azines (35, R = cyclopropyl, Et) [117], 6-aryloxy-2-hydroxyalkyI-3(27/)-pyri-dazinones [118], 3-halo-6-hydrazinopyridazines of type (36, R = substituted amino) [119], Ar-2-isoxazolylmethyl-substituted 3-iminopyridazines (37) [ 120], carbamates derived from 3,6-bis(hydroxymethyl)-4-pyridazinones (38, R = alkyl, Ph) [121], and iminodihydropyridazine derivatives (39, R1 = acyl R2 = H,MeS R3 = aryl) [122, 123]. In Hungary, antidepressant activity has been observed with some 3,6-disubstituted pyridazines of type (40) [124]. 

The biotransformation of clofexamide (4.33, Fig. 4.4), a compound with anti-inflammatory and antidepressant activities, was investigated in rats [18]. About 15% of the dose administered was found in urine as 2-(4-chlorophe-noxy)acetic acid (4.37). This metabolite was formed via the secondary amine 4.34, the primary amine 4.35, and the acid 4.36 resulting from oxidative deamination. However, direct formation of 2-(4-chlorophenoxy)acetic acid (4.37) from the parent compound (4.33) cannot be excluded. Clofexamide and its metabolite 4.34 also underwent hydroxylation on the aromatic ring, but these hydroxylated metabolites did not appear to be hydrolyzed. 

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