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Chapter 3. Progress in Antidepressant Drugs
Chapter 3. Progress in Antidepressant Drugs David W. Robertson and Ray W. Fuller Lilly Research Laboratories, Indianapolis, Indiana 46285 Jntroduction - Depression is the most frequently diagnosed psychiatric disorder, and despite the recent availability of several new medications for its treatment, this disease continues to be a major public health problem. Advances in antidepressant drugs were reviewed recently in this series (1). Several additional recent reviews have been published: The role of animal models of depression in the search for new drug candidates continues to be assessed (2-4). The focus of several reviews was the important role of serotonin (5HT) in depression; several mechanistically distinct classes of antidepressants all lead to enhancement of 5HT neurotransmission (5-7). This chapter will focus on the most recent progress in the discovery and development of several mechanistically defined classes of potential antidepressant drugs, and preference will be given to citations which appeared in 1990. Monoamine W k e In hibitors - Although the first selective 5HT uptake inhibitors were described in the mid-l970s, only within the past several years have these compounds been successfully marketed as antidepressants (8). Fluoxetine u> has been marketed for several years in many counties; fluvoxamine is marketed in some counties, and sertraline and paroxetine are currently being launched in multinational arenas. Many experimental approaches have demonstrated that all of these compounds are highly selective 5HT uptake inhibitors both in vitro and in vivo. Moreover, all appear to be clinically effective antidepressants (8). Although the efficacy of these compounds appears to be comparable to the tricyclic antidepressants, these selective 5HT uptake inhibitors have considerably lower affinities for neurotransmitter receptors than do the tricyclic antidepressants. Clinically, these lower affinities result in fewer anti-adrenergic, anticholinergic and antihistaminergic side effects for the new 5HT uptake inhibitors compared to tricyclic antidepressants. The principal differences among fluoxetine, sertraline, and paroxetine relate to the clinical doses and half-lives in man (9,lO). The preclinical pharmacology of fluoxetine has been reviewed (1 1). The absolute configurations of the enantiomers of fluoxetine have been reported previously (12), and the biochemical and pharmacological profiles of the R and S enantiomers of fluoxetine were reviewed; both enantiomers are virtually identical to the racemate as 5HT uptake inhibitors and display eudismic ratios near unity both in vitro and in vivo (13). Norfluoxetine, the N-desmethyl metabolite of fluoxetine, is essentially equipotent with fluoxetine as a 5HT uptake inhibitor. The homochiral enantiomers of norfluoxetine have been prepared recently and studied as 5HT uptake inhibitors (14). In rat brain cortical synaptosomes, the R and S enantiomers of norfluoxetine inhibited 5HT uptake with IC50 values of 484 and 54 nM, respectively. Thus, as an inhibitor of 5HT uptake, S-norfluoxetine is equipotent with the two enantiomers of fluoxetine, but is 9 times more potent than R-norfluoxetine in vitro (14). This increased eudismic ratio of norfluoxetine was also apparent following in vivo comparisons of the two enantiomers (15). Fluoxetine inhibits cytochrome P-450 which leads to some drug-drug interactions, and the most widely noted have been interactions with tricyclic antidepressants; the clinical data have been reviewed recently (1 6,17). Combinations of fluoxetine with monoamine oxidase (MAO) inhibitors such as tranylcypromine or phenelzine lead to a "serotonergic syndrome" in man, the symptoms of which include myoclonus, tremor, and confusion (18). This interaction probably results from both pharmacological interventions elevating the concentrations of 5HT in the synaptic cleft by mechanistically distinct avenues. This interaction between 5HT uptake inhibitors
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and MA0 inhibitors may be general, and has also been reported for the combination of clorgyline and clomipramine (19). Because 5HT uptake inhibitors lead to an enhancement of 5HT neurotransmission in all 5HT neurons and brain regions, they may be useful in treating many affective and behavioral disorders. For example, clomipramine has been marketed for treatment of both depression and obsessive-compulsive disorder, and reviews have appeared on its clinical pharmacology (20.21). In a double-blind, placebo-controlled mal, sertraline was shown to be effective in treatment of obsessive-compulsive disorder and its effects resembled those seen previously with fluvoxamine, fluoxetine, and zimelidine. The selective 5HT uptake inhibitors appear to consistently perform better than tricyclic antidepressants in treatment of obsessive-compulsive disorder (22). In a placebo-controlled, double-blind study, fluvoxamine reduced the number of panic attacks and decreased avoidance behavior (23). A double-blind placebo-controlled study of citalopram in non-depressed patients with Alzheimer's disease was reported. Although this selective 5HT uptake inhibitor did not improve memory or other intellectual functions, it did improve emotional bluntness, confusion, and agitation (24). Use of fluoxetine in the treatment of obesity continues to be studied, and placebo-controlled mals suggest it produces weight loss by decreasing caloric intake (25,26). Fluoxetine and sertraline continue to be examined as adjunctive therapies in the treatment of alcoholism (27,28).
2
1
9
Several recent publications have described additional 5HT uptake inhibitors. JO- 1017
(2) selectively inhibits 5HT uptake and has high affinities for [3H]-imipramine and [3H]-
paroxetine binding sites in brain tissue. The compound has been examined in several rodent models which are reported to detect potential antidepressant drugs: the compound decreases escape failures in the learned helplessness test in rats and immobility times in behavioral despair tests in mice (29). Early clinical studies suggest the compound is an effective, welltolerated antidepressant (30,31). MDL-28618A (3) is a conformationally defined analogue of fluoxetine, and the dextrorotatory enantiomer is 10 times more potent than the levorotatory isomer as a 5HT uptake inhibitor (32). The SAR and some aspects of the phar-
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Robertson. Fuller g5
macology of McN-5652-Z (4) were reported. It is a potent inhibitor of 5HT uptake in vitro, and virtually all of the activity resides in the truns-(+)-6S,lObR enantiomer; the eudismic ratio is approximately 150. It is one of the most potent agents yet described (ED50= 80 @kg, i.p.) in the mouse 5-hydroxytryptophan-inducedhead-twitch assay (33). The SAR of venlafaxine was reported, and the optimal compounds possessed halogen or methoxy substituents at the 3- and/or 4-positions of the aromatic ring. Venlafaxine is a relatively nonselective inhibitor of 5HT and norepinephrine (NE)uptake in vitro (Ki values were 210 and 640 nM, respectively). The eudismic ratio of the enantiomers of venlafaxine is less than 3 for inhibition of either 5HT or NE uptake (34). An analogue of venlafaxine, Ro 15-8081 (0, is a nonselective inhibitor of 5HT and NE uptake, and has been studied clinically as a dual analgesic-antidepressant (35). Its bicyclic metabolite, 2, is a selective inhibitor of NE uptake, and compared to the parent compound, 6, it was considerably less potent as an analgesic agent in animal models; these data suggest that 5HT uptake inhibition plays a role in the analgesic effects of the parent compound (35). Dapoxetine a) is a structurally distinct, selective 5HT uptake inhibitor that potently suppresses food intake in three different rodent paradigms (36). LY233708 Ce, is a structural hybrid of piperazine-derived 5HT uptake inhibitors and aminotetralin 5HTla agonists (37,38). Both dapoxetine and LY233708 are potent, selective 5HT uptake inhibitors in vitro and in vivo, and display very low or no affinities for the neurotransmitter receptors which mediate the side effects of ticyclic antidepressants. The dextrorotatory enantiomer of lQ (LY248686) equipotently inhibited 5HT and NE inhibits both 5HT and NE reuptake in virro (39). Compound uptake in an ex vivo paradigm with ED50 values of 12.2 and 14.6 m a g , P.o., indicating that the balanced in vitro uptake inhibition was also manifest in vivo (39).
In order to more fully understand the biochemical basis for the efficacies of antidepressant drugs, a variety of mtium-labeled ligands has been used to study the 5HT transporter, including paroxetine, citalopram, fluoxetine, imipramine, and several imipramine analogues (8). [3H]-Paroxetinewas shown to be superior to [3H]-imipramineas a ligand for the 5HT transporter in that the former compound labels a homogeneous population of binding sites (40); [3H]-paroxetinewas also superior to [3H]-imipraminefor autoradiographic localization of the 5HT transporter (41). ['HI-Sertraline was reported recently, and it selectively X 11 x = O C [ ~ H ~ ] labels the 5HT uptake carrier (42). ['HINHCH, = c[3H3] 6-nitroquipazine is also a useful ligand 0 for the 5HT uptake carrier. The l3 x = "2511 compound labels the 5HT transporter in human platelets and rat cortical membranes with subnanomolar Kd values, and with low nonspecific binding (43-45). Because the compound has appropriate in vivo kinetics and penetrates the blood-brain-barrier more readily than other 5HT uptake inhibitors such as cyanoimipramine or paroxetine, 6-nitroquipazine may be a useful template for the design of 5HT uptake inhibitors which are suitable for PET or SPECT imaging (46). Two groups have described the successful synthesis of [llCI-labeled citalopram for non-invasive in vivo studies of 5HT uptake sites in human brain using PET
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imaging (47,48). [)H]-Nisoxetine and [3H]-tomoxetine(12)are the first selective radioligands for the NE transporter (4930). Finally, 13,an [lsI]-labeled congener of tomoxetine, binds with high affinity and selectivity to the NE transporter, and enables the rapid autoradiographic visualization of NE cell bodies and fibers (51). a-3 A d r e n umor Antagonists - The medicinal chemistry and pharmacology of a-2 adrenoceptor antagonists have been actively explored in recent years. The presynaptic a-2 adrenoceptor appears to be the terminal autoreceptor of noradrenergic neurons, and blockade of these receptors represents a theoretically attractive means of increasing noradrenergic drive. Therefore, a-2 adrenoceptor antagonists and inhibitors of the NE uptake can-ier (such as tricyclic antidepressants) should increase synaptic concentrations of norepinephrine by mechanistically distinct paths (52). Mianserin is an antidepressant drug whose mechanism of action may be blockade of presynaptic a-2 receptors on NE nerve terminals, resulting in increased release of NE (53). However, mianserin has multiple pharmacological actions, which complicate interpretations about the possible value of selective a-2 adrenoceptor antagonists in the treatment of depression.
The probable existence of a-2 adrenoceptor subtypes continues to receive considerable attention, and a-2a and a-2b adrenoceptors have been proposed based upon radioligand binding studies (54). Moreover, Regan and colleagues have demonstrated the existence of multiple genes which encode for a-2 adrenoceptors (55). These a-2 adrenoceptor subtypes may mediate functionally distinct processes; for example, a-2a, but not a-2b, adrenoceptor antagonists appear to block a adrenoceptor-mediatedinhibition of insulin release in the rat pancreas (56,57). The design of highly selective compounds which will assist in the elucidation of these purported a-adrenoceptor subtypes continues to be a formidable objective. The imidazoline derivative, idazoxan (14).is the prototypic a-2 antagonist. It has served as a template for much of the recent a-2 antagonist medicinal chemistry. The SAR of a series of tetrahydroisoquinolinylimidazolines related to idazoxan was reported (58). In this series, some derivatives were found to be modestly selective as antagonists of ['HIidazoxan labeled sites, whereas some had selectivity as antagonists of ['HI-yohimbine labeled sites in brain tissue. On the basis of radioligand binding studies, the 8-chloro derivative fi demonstrated a 7-fold selectivity for a-2 versus a-1 adrenoceptors. Moreover,
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the compound displayed 36-fold selectivity as an antagonist of [)H]-idazoxan-versus ['HIyohimbine-labeled a-2 adrenoceptors. As determined by functional studies in the guinea pig ileum, the compound was a partial agonist at a-2 adrenoceptors (58). Benzodioxane derivatives may function as antagonists at either a-2 or a-1 adrenoceptors (e.g., idazoxan or WB 4101 U), respectively). Compound fl,the analogue of 16 in which a trans phenyl group has been placed at position 3 of the dioxane ring, is substantially more selective than 16 for a-1 adrenoceptors. This was primarily the result of a phenyl-induced reduction in affinity for a-2 receptors, presumably due to a sterically deleterious interactions of the phenyl moiety with the a-2 receptor (59). The selectivity ratios of 16 and 12 for a- 1 versus a-2 receptors were 794 and 23442, respectively. The imidazole derivative is a potent antagonist of a-2 adrenoreceptors, with a pA2 of 8.73 versus clonidine-induced inhibition of electrically simulated contractions of the guinea pig ileum. Importantly the a2/a- 1 adrenoceptor selectivity ratio was 8 1. Finally, the compound was also reported to be a weak inhibitor of the presynaptic NE transporter; by promoting the release of NE and blocking its reuptake, such a compound would be expected to enhance noradrenergic
Chap. 3
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Robertson. Fuller 27
function markedly (60). Napamezole (U) has been previously described as an a - 2 adrenoceptor antagonist with modest selectivity for a-2 versus a- 1 adrenoceptors. Full reports on the in virro (61) and in vivo (62) pharmacology of napamezole were recently published; in vitro studies demonstrated that napamezole weakly inhibits 5HT reuptake. However, in vivo, the compound appeared to block a-2 adrenoceptors and inhibit 5HT uptake at comparable doses, suggesting that the compound could affect two key neurotransmitters simultaneously. The tetracyclic compound 2Q is a structural hybrid between rauwolscine and the previously reported a-2 adrenoceptor antagonist W Y 26703 (2L). The 8aR,12aS,13aS isomer is over three orders of magnitude more potent than its optical antipode, and the a-2/a-l selectivity ratio of the compound is in excess of 15000 (63,64).
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Compound 22,a structural hybrid of reboxetine and idazoxan, was synthesized to combine the NE uptake-inhibiting properties of the former drug and the a-2 adrenoreceptor blocking properties of the latter drug. Unfortunately, 22 and several analogs were not active either as a-2 receptor antagonists or as norepinephrine uptake inhibitors (65). 5HTla Agonists - A general discussion of the medicinal chemistry of 5HTla agonists can be found in Chapter 11 of this volume (66). Recent clinical studies have found that buspirone, gepirone, and ipsapirone are effective antidepressants (67-72). These compounds appear to exert their anxiolytic effects by their actions as 5HTla partial agonists; moreover, it has been suggested that the same molecular action accounts for their more recently discovered antidepressant activities. However, an alternative mechanism for their antidepressant actions has been proposed. These compounds are metabolized extensively (73,74)to 1-(2-pyrimidinyl)piperazine (1-PP). This metabolite has little affinity for 5HT receptors (73), and it is not thought to be involved in the anxiolytic effects produced by administration of the parent drug (75). However, based upon its pharmacological actions, the metabolite may be involved in the antidepressant actions of these structurally related 5HT1a agonists. 1-PP is a relatively potent a-2 adrenoceptor antagonist (73,7678). In blood and brain of animals treated with buspirone or gepirone, 1-PP levels were higher and persisted longer than parent drug (73). In blood of humans treated with buspirone, the metabolite I-PP is present at markedly higher concentrations than buspirone (73). In vivo blockade of a-2 adrenoceptors occurs after buspirone or gepirone administration, due to the formation and persistence of the metabolite 1-PP (76,7942). As described in a previous section of this
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chapter, a variety of a-2adrenoceptor antagonists are under development for the treatment of depression (83). Thus the pharmacological actions of the metabolite 1-PP complicates mechanistic interpretations relative to the antidepressant effects of presently available SHT1a partial agonists. Further studies with additional SHTla receptor agonists, particularly with agonists of other structural types that do not liberate pharmacologically active substances, should clarify the mechanisms involved in the antidepressant actions of these drugs. Some animal studies support the hypothesis that SHTla receptor agonists have (8intrinsic antidepressant effects. For example, 8-hydroxy-2-(di-N-propylamino)tetralin OH-DPAT, 24), a prototypic full agonist at 5HTla receptors, was active in a learned helplessness behavior paradigm in rats (84).This model is often considered to be predictive of clinical antidepressant activity. 8-OH-DPAT, as well as piperazine-derived SHTla partial agonists, reduced immobility time in the forced swim test in rats (85). These behavioral studies with SHTla receptor agonists in rats support earlier findings (86,87).The 8methylthio analog (2) of 8-OH-DPAT was reported to be more potent than 8-OH-DPAT itself (88). The 5-fluoro derivative (26) of 8-OH-DPAT was reported to be a relatively impotent antagonist of SHTla receptors (89).
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24 X = O H , Y = H
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22 28
X=SCH3,Y=H X=OH,Y=F
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The benzodioxane derivative MDL 72832 (2T,has been previously reported to be a partial agonist at SHTla receptors (90). In a variety of assays, the eudismic ratio was approximately 32, and the levorotatory isomer was the more potent enantiomer (90,91).A is also a potent SHTla partial agonist homologue of this compound, MDL 73005EF and is active in animal models of anxiety (92). Structural modification of the a-2 adrenoceptor antagonist (SKF 86466) resulted in 3, which had relatively high and balanced affinities for both a-2 and SHTla receptors (pKi values were 8.1 and 7.6, respectively (93).In addition to SHTla agonists, preliminary clinical trials suggest that the SHT2 receptor antagonists ritanserin (94)and nefazodone (95)may have clinical efficacy in the treatment of depression.
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Other mechanistic approaches - Inhibitors of M A 0 have been used for more than 30 years in the treatment of depression. Because of potentially lethal hypertensive crises following ingestion of foods containing sympathomimetic amines, MA0 inhibitors are used relatively infrequently in the treatment of major depression (96). However, M A 0 inhibitors currently used to treat depression in the U.S. are irreversible inhibitors, and are relatively nonselective a reversible inhibitor for the two isozymes of MAO, type A and type B. Moclobemide highly selective for type A MAO, was recently introduced to the marketplace in some countries (97). Other selective and reversible MAO-A inhibitors, including brofdromine
u,
Antidepressants
Chap 3
Robertson, Fuller 29
(m,
are under development (98). The fact that these compounds appear to be effective antidepressants, without the risk of severe cardiovascular side effects that plague the older MA0 inhibitors, may lead to a more widespread utilization of MA0 inhibitors (99).
Rolipram (s)is a prototypic inhibitor of the type IV, cGMP-insensitive phosphodiesterase (PDE), an isoform of phosphodiesterase that appears to be particularly important in modulating CAMP metabolism in the CNS (100-102). Rolipram has demonstrated antidepressant efficacy in over 14 double-blind clinical mals (103- 105). An SAR study of rolipram, and a topographical model of its binding site on the phosphodiesterase isozyme, were presented (106). For a wide range of rolipram analogues, there were highly significant correlations between the potencies of compounds to antagonize reserpine-induced hypothermia in mice or induce head twitches in rats, and their potencies as antagonists of [3H]-rolipram binding ex vivo (107). These data, when coupled with the strong evidence that [3H]-rolipram binds specifically to the PDE isozyme, lend further support to the hypothesis that the behavioral effects of rolipram are mediated by inhibition of type IV,cGMP-insensitive PDE (108).
6, 33
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33
MDL 26,479 (3) does not inhibit monoamine uptake camers in vitro, but it does antagonize Ro 4- 1284 induced hypothermia and reserpine-induced ptosis in mice, effects usually seen with potent monoamine uptake inhibitors (109). When given chronically, both and desipramine attenuated NE enhancement of inhibitory responses to GABA on Purkinje neurons. Unlike desipramine, acute treatment with 3decreased noradrenergic enhancement of GABA inhibition, suggesting 3might have a faster onset of antidepressant action clinically (109). Based upon animal studies, substances that reduce neurotransmission at the NMDA (N-methyl-D-aspartate) receptor complex (1 10) may represent a new class of antidepressant drugs. A variety of NMDA modulators mimicked the effects of antidepressant drugs in reducing the duration of immobility in a forced-swim test in mice, including 2-amino-7phosphonoheptanoic acid (AP-7), a competitive NMDA receptor antagonist; dizolcipine (MK-801), a noncompetitive NMDA receptor antagonist; and 1-aminocyclopropanecarboxylic acid, a partial agonist at strychnine-insensitive glycine receptors (1 11). A series reduced immobility in Porsolt’s behavioral of 4-amino-[ 1,2,4]-triazolo-[4,3-a]-quinoxalines despair model in rats, a preclinical model designed to detect antidepressants (1 12). These compounds were potent adenosine A1 and A2 receptor antagonists, and this was presumed to be the biochemical mechanism of their behavioral effects; X was one of the optimal compounds (1 12). Captopril exhibited activity comparable to imipramine in the learned helplessness paradigm in rats (1 13). Moreover, a variety of anecdotal clinical reports
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suggest that captopril exhibits mood-elevating and antidepressant properties in man (114). Determination of whether ACE inhibitors, or the newly developed angiotensin I1 receptor antagonists (115), can be used to treat affective disorders will require carefully controlled, prospective clinical trials. Conclusions - The decade of the 1990s will witness the introduction of a wide variety of additional antidepressant drugs. Many of these compounds will be advances in that they will produce fewer side effects than tricyclic antidepressants. However, development of compounds which produce therapeutic effects more rapidly, or in greater percentage of patients, than tricyclic antidepressantsremain elusive goals. Discovery of such compounds will probably require a more sophisticated understanding of the fundamental biochemical aberrations which underlie depression. Feferenca 1.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
13. 14. 15.
16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
J.L. Ives and J. Heym, Annu. Rep. Med. Chem., 24, 21 (1989). P. Willner, Pharmacol. Ther., 45,425 (1990). M. Bourin, Fundam. Clin. Pharmacol., 4.49 (1990). J.S. Andrews and D.N. Stephens, Pharmacol. Ther., 0 , 2 6 7 (1990). P. Blier, C. de Montigny, and Y. Chaput, J. Clin. Psychiatry, 2 [4. Suppl], 14 (1990). D.S. Chamey, J.H. Krystal, P.L. Delgado, and G.R. Heninger, Annu. Rev. Med., Q, 437 (1990). L.H. Price, D.S. Chamey, P.L. Delgado, W.K. Goodman, J. H. Krystal, S.W. Woods, and G.R. Heninger, J. Clin. Psychiatry, fi [4, Suppl], 44 (1990). R.W. Fuller and D.T. Wong, Ann. N.Y. Acad. Sci., hnn. 68 (1990) K. Rickels and E. Schweizer, J. Clin. Psychiatry, 2 [12, Suppl B], 9 (1990). F.W. Reimherr, G. Chouinard, C.K. Cohn, J.O. Cole, T.M. Itil, Y.D. LaPierre, H.L. Masco, and J. Mendels, J. Clin. Psychiatry, 51 (Suppl B), 18 (1990). R.W. Fuller, D.T. Wong, and D.W. Robertson, Med. Res. Rev., 11,17 (1991). 1412 D.W. Robertson, J.H. Krushinski, R.W. Fuller, and J.D. Lander, J. Med. Chem., (1988). D.T. Wong, R.W. Fuller, and D.W. Robertson, Acta Pharm. Nord., 2,171 (1990). D.W. Robertson, J.H. Krushinski, L.R. Reid, F.P. Bymaster, and D.T. Wong, Annual Meeting of The American Society for Pharmacology and ExperimentalTherapeutics, San Diego, California, August 16-20, 1991. D.T.Wong, L.R. Reid, F.P. Bymaster, J.H. Krushinski, and D.W. Robertson, Annual Meeting of The American Society for Pharmacology and Experimental Therapeutics, San Diego, California, August 16-20, 1991. D.A. Ciraulo and R. I. Shader, J. Clin. Psychopharmacol.,111.48 (1990). D.A. Ciraulo and R. I. Shader, J. Clin. Psychopharmacol.,111, 213 (1990). 222 (1990). J. P. Feighner, W.F. Boyer, D.L. Tyler, and R.J. Neborsky, J. Clin. Psychiatry, 954 (1982). T.R. Insel, B.F. Roy, and R.M. Cohen, Am. J. Psychiatry, M.R. Trimble, J. Clin. Psychiatry, 2 18, Suppl], 51 (1990). M.D. Peters, S.K. Davis, and L.S. Austin, Clinical Pharmacy, 9, 165 (1990). G. Chouinard, W. Goodman, J. Greist, M. Jenike, S. Rasmussen, K. White, E. Hackett, M. Gaffney, and P.A. Bick, Psychopharmacol. Bulletin, 24,279 (1990). J.A. Den Boer and H.G.M. Westenberg, Psychopharmacology,1112.85 (1990). I. Karlsson, Clinical Neuropharmacol., U [Suppl 21, 99 (1990). H. Rjl, H.P.F. Koppeschaar, F.L.A. Willekens, 1. Op de Kamp, H. D. Veldhuis, and A.E. 237 (1991). Meinders, International Journal of Obesity, M.D. Marcus, R.R. Wing, L. Ewing, E. Kern. M. McDermott, and W. Gooding, Am. J. Psychiatry, J&, 876 (1990). C.A. Naranjo, K.E. Kadlec, P. Sanhueza. D. Woodley-Remus,and E.M. Sellers, Clin. Pharmacol. Ther., 42 490 (1990). K. Gill, 2. Amit, and B.K. Koe, Alcohol, 5.349 (1988). CJ. Gouret, R. Porsolt, J.G. Wettstein, A. Puech, C. Soulard, X. Pascaud, and J.L. Junien, Arzneim.-Forsch./Drug Res., 633 (1990). B. Earley, M. Burke, B.E. Leonard, CJ. Gouret, and J.L. Junien, Psychopharmacology (Berlin), 1Q1 [Suppl.] S17 (1990). Y.Guillon, J.F. Dreyfus. B. Scherrer, and Y.Bogaievsky, 17th Congress of Collegium International Neum-Psychopharmacologicum,Kyoto, Japan, September 10-14,1990,
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32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43.
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45. 46. 47. 48. 49. 50. 51.
52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63.
64. 65.
66. 67. 68. 69. 70. 71.
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z,
Kl
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m,
m, m,
m,
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m,
m,
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Section I-CNS Agents
32 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 1oQ. 105. 106. 107. 108. 109.
110. 111. 112. 113. 114. 115.
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S.W. Jenkins, D.S. Robinson. L.F. Fabre, Jr.. J.J. Andary, M.E. Messina, and L.A. Reich, J. Clin. Psychopharmacol.,1Q [3, Suppl], 77s (1990). S. Caccia, I. Conti, G. Vigano, and S. Garattini, Pharmacology, 2 , 46 (1986). G. Bianchi and S. Garattini, Eur.J. Pharmacol., 142, 343 (1988). R.E. Gammans, R.F. Mayol, and J.A. Labudde, Am. J. Med., BQ [3B Suppl], 41 (1896). 113 (1987). P. Giral, P. Soubrie, and A.J. Puech, Eur. J. Pharmacol., T.J. Rimele, D.E. Henry, D.K.H. Lee, G. Geiger, R J . Heaslip, and D. Grimes, J. Pharmacol. Exp. Ther., 771 (1987). M. Gobbi, E. Frittoli, and T. Mennini, Eur. J. Pharmacol.. 18Q,183 (1990). A.J. Gower, Brit. J. Pharmacol., @, 726P (1986). G. Bianchi, S. Caccia, F.D. Vedova, and S.Garattini, Eur. J. Pharmacol., 111,365 (1988). G. Engberg, J. Neural. Trans., X , 9 1 (1989). R.W. Fuller and K.W. Perry, J. Pharmacol. Exp. Ther., m,50 (1989). R.M. Pinder and J.M. Sitsen, Psychopharmacol. Ser., 1,107 (1987). 135 (1990). P. Martin, R.J. Beninger, M. Hamon, and A.J. Puech, Behav. Brain Res., 3, S. Wieland and I. Lucki, Psychopharmacology 1111,497 (1990). L. Cervo and R. Samanin, Eur. J. Pharmacol., 144,223 (1987). G.A. Kennett, C.T. Dourish, and G. Curzon, Eur. J. Pharmacol., .& 265 (1987). J.M. Schaus, R.D. Titus, D.L Huser, C.S. Hoechstetter, D.T. Wong, R.D. Marsh, and R.W. Fuller, Twentieth Annual Meeting of the Society for Neuroscience, 16,529 (1990). S.E. Hillver, L. Bjork, Y.L. Li, B. Svensson, S . Ross, N.E. Anden, and U. Hacksell, J. Med. Chem., 1544 (1990). A.K. Mir, M. Hibert, M.D. Tricklebank, D.N. Middlemiss, E.J. Kidd and J.R. Fozard, Eur. J. Pharmacol., &Q, 107 (1988). M. Hibert, M.W. Gittos, D.N. Middlemiss, A.K. Mir, and J.R. Fozard, J. Med. Chem., X, 1087 (1988). P.C. Moser, M.D. Tricklebank, D.N. Middlemiss, A.K. Mir, M.F. Hibert, and J.R. Fozard, Br. J. Pharmacol., $@, 343 (1990). R.D. Clark, K.K. Weinhardl, J. Berger, L.E. Fischer, C.M. Brown, A. Mackinnon, A J . Kilpabick, and M. Spedding, J. Med. Chem., 2 , 6 3 3 (1990). A. Stokland, M. Larsson, A. Manhem, and A. Forsman, Psychopharmacology, B9 (1990). M.F. D'Amico, D.L. Roberts, D.S. Robinson, U.E. Schwiderski, and J. Copp, Psychopharmacol. Bull., 26, 147 (1990). C. Clary, L.A. Mandos, and E. Schweizer, I. Clin. Psychiat. 51,226 (1990). R.G. Priest, Acta Psychiat. Scand., [Suppl], 39 (1990). 131 (1990). J. F r i k . T. Becker, V. Ziegler, G. Laux, and P. Riederer, Pharmacopsychiatry 2, B.A. Callingham, Clinical Neuropharmacol.,JJ [Suppl 21, 192 (1990). D.W. Robertson and D.B. Boyd, "Advances in Second Messenger and Phosphoprotein Research", Vol. 24, SJ. Strada and H. Hidaka, Ed., Raven Press, 1991, in press. R.AJ. Challis and C.D. Nicholson, Br. J. Pharmacol., $@,47(1990). M.E. Whalin, R.L. Garrett, WJ. Thompson, and SJ. Strada, Second Messengers and Phosphoproteins, u,31 1 (1989). F. Eckmann, K. Fichte, U. Meya, and M. Sastre-Y-Hernandez,Curr. Ther. Res., 4 , 2 9 1 (1988). [Suppl] 246 (1988). D.L. Dunner. D.H. Avery, S.R. Dager and A. Khan, Psychopharmacol., U. Meya, H. Wachtel, and M. Sastre-y-Hernandez,17th Congress of Collegium Internationale Neuro-Psychopharmacologicum,Kyoto, Japan, September 10-14.1990. M.C. Marivet, J.J. Bourguignon, C. Lugnier, A. Mann, J.C. Stoclet, and C.G.Wermuth, J. Med. Chem., 2,1450 (1989). 17 (1990). R. Schmiechen, H.H. Schneider,and H. Wachtel, Psychopharmacology (Berlin), H.H. Schneider. G. Pahlke, and R. Schmiechen In: Heilmeyer LMG (ed)Signal transduction and protein phosphorylation, NATO AS1 Series A, Vol. 135, Plenum Press, New York, N.Y., 1988, p. 81. S.M. Sorensen, J.M. Zwolshen, and J.M. Kane, Neuropharmacology B, 555 (1990). For a recent review on the medicinal chemistry of excitatory amino acid antagonists,see: G. Johnson and C.F. Bigge, Annu. Rep. Med. Chem., Chapter 2 (1991). R. Trullas and P.Skolnick, Eur. J. Pharmacol., 181,1 (1990). R. Sarges, H.R. Howard, R.G. Browne, L.A. Lebel. P.A. Seymour, and B.K. Koe, J. Med. Chem., 2 , 2 2 4 0 (1990). P. Martin, J. Massol, and A.J. Puech, Biol. Psychiatry, 22,968 (1990). L. Germain and G. Chouinard, Biol. Psychiatry, 2 , 4 8 9 (1989). W.J. Greenlee and P.K.S. Siegl, Annu. Rep. Med. Chem., %,63 (1991).
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Section I-CNS Agents
24
McCall, Ed.
and MA0 inhibitors may be general, and has also been reported for the combination of clorgyline and clomipramine (19). Because 5HT uptake inhibitors lead to an enhancement of 5HT neurotransmission in all 5HT neurons and brain regions, they may be useful in treating many affective and behavioral disorders. For example, clomipramine has been marketed for treatment of both depression and obsessive-compulsive disorder, and reviews have appeared on its clinical pharmacology (20.21). In a double-blind, placebo-controlled mal, sertraline was shown to be effective in treatment of obsessive-compulsive disorder and its effects resembled those seen previously with fluvoxamine, fluoxetine, and zimelidine. The selective 5HT uptake inhibitors appear to consistently perform better than tricyclic antidepressants in treatment of obsessive-compulsive disorder (22). In a placebo-controlled, double-blind study, fluvoxamine reduced the number of panic attacks and decreased avoidance behavior (23). A double-blind placebo-controlled study of citalopram in non-depressed patients with Alzheimer's disease was reported. Although this selective 5HT uptake inhibitor did not improve memory or other intellectual functions, it did improve emotional bluntness, confusion, and agitation (24). Use of fluoxetine in the treatment of obesity continues to be studied, and placebo-controlled mals suggest it produces weight loss by decreasing caloric intake (25,26). Fluoxetine and sertraline continue to be examined as adjunctive therapies in the treatment of alcoholism (27,28).
2
1
9
Several recent publications have described additional 5HT uptake inhibitors. JO- 1017
(2) selectively inhibits 5HT uptake and has high affinities for [3H]-imipramine and [3H]-
paroxetine binding sites in brain tissue. The compound has been examined in several rodent models which are reported to detect potential antidepressant drugs: the compound decreases escape failures in the learned helplessness test in rats and immobility times in behavioral despair tests in mice (29). Early clinical studies suggest the compound is an effective, welltolerated antidepressant (30,31). MDL-28618A (3) is a conformationally defined analogue of fluoxetine, and the dextrorotatory enantiomer is 10 times more potent than the levorotatory isomer as a 5HT uptake inhibitor (32). The SAR and some aspects of the phar-
6'
2
N(CH3)2 H
4
6
R=H,Z=CH30 R=OH,Z=CI
Antidepressants
Chap. 3
Robertson. Fuller g5
macology of McN-5652-Z (4) were reported. It is a potent inhibitor of 5HT uptake in vitro, and virtually all of the activity resides in the truns-(+)-6S,lObR enantiomer; the eudismic ratio is approximately 150. It is one of the most potent agents yet described (ED50= 80 @kg, i.p.) in the mouse 5-hydroxytryptophan-inducedhead-twitch assay (33). The SAR of venlafaxine was reported, and the optimal compounds possessed halogen or methoxy substituents at the 3- and/or 4-positions of the aromatic ring. Venlafaxine is a relatively nonselective inhibitor of 5HT and norepinephrine (NE)uptake in vitro (Ki values were 210 and 640 nM, respectively). The eudismic ratio of the enantiomers of venlafaxine is less than 3 for inhibition of either 5HT or NE uptake (34). An analogue of venlafaxine, Ro 15-8081 (0, is a nonselective inhibitor of 5HT and NE uptake, and has been studied clinically as a dual analgesic-antidepressant (35). Its bicyclic metabolite, 2, is a selective inhibitor of NE uptake, and compared to the parent compound, 6, it was considerably less potent as an analgesic agent in animal models; these data suggest that 5HT uptake inhibition plays a role in the analgesic effects of the parent compound (35). Dapoxetine a) is a structurally distinct, selective 5HT uptake inhibitor that potently suppresses food intake in three different rodent paradigms (36). LY233708 Ce, is a structural hybrid of piperazine-derived 5HT uptake inhibitors and aminotetralin 5HTla agonists (37,38). Both dapoxetine and LY233708 are potent, selective 5HT uptake inhibitors in vitro and in vivo, and display very low or no affinities for the neurotransmitter receptors which mediate the side effects of ticyclic antidepressants. The dextrorotatory enantiomer of lQ (LY248686) equipotently inhibited 5HT and NE inhibits both 5HT and NE reuptake in virro (39). Compound uptake in an ex vivo paradigm with ED50 values of 12.2 and 14.6 m a g , P.o., indicating that the balanced in vitro uptake inhibition was also manifest in vivo (39).
In order to more fully understand the biochemical basis for the efficacies of antidepressant drugs, a variety of mtium-labeled ligands has been used to study the 5HT transporter, including paroxetine, citalopram, fluoxetine, imipramine, and several imipramine analogues (8). [3H]-Paroxetinewas shown to be superior to [3H]-imipramineas a ligand for the 5HT transporter in that the former compound labels a homogeneous population of binding sites (40); [3H]-paroxetinewas also superior to [3H]-imipraminefor autoradiographic localization of the 5HT transporter (41). ['HI-Sertraline was reported recently, and it selectively X 11 x = O C [ ~ H ~ ] labels the 5HT uptake carrier (42). ['HINHCH, = c[3H3] 6-nitroquipazine is also a useful ligand 0 for the 5HT uptake carrier. The l3 x = "2511 compound labels the 5HT transporter in human platelets and rat cortical membranes with subnanomolar Kd values, and with low nonspecific binding (43-45). Because the compound has appropriate in vivo kinetics and penetrates the blood-brain-barrier more readily than other 5HT uptake inhibitors such as cyanoimipramine or paroxetine, 6-nitroquipazine may be a useful template for the design of 5HT uptake inhibitors which are suitable for PET or SPECT imaging (46). Two groups have described the successful synthesis of [llCI-labeled citalopram for non-invasive in vivo studies of 5HT uptake sites in human brain using PET
-Q
&
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Section I-CNS Agents
McCall, Ed.
(u)
imaging (47,48). [)H]-Nisoxetine and [3H]-tomoxetine(12)are the first selective radioligands for the NE transporter (4930). Finally, 13,an [lsI]-labeled congener of tomoxetine, binds with high affinity and selectivity to the NE transporter, and enables the rapid autoradiographic visualization of NE cell bodies and fibers (51). a-3 A d r e n umor Antagonists - The medicinal chemistry and pharmacology of a-2 adrenoceptor antagonists have been actively explored in recent years. The presynaptic a-2 adrenoceptor appears to be the terminal autoreceptor of noradrenergic neurons, and blockade of these receptors represents a theoretically attractive means of increasing noradrenergic drive. Therefore, a-2 adrenoceptor antagonists and inhibitors of the NE uptake can-ier (such as tricyclic antidepressants) should increase synaptic concentrations of norepinephrine by mechanistically distinct paths (52). Mianserin is an antidepressant drug whose mechanism of action may be blockade of presynaptic a-2 receptors on NE nerve terminals, resulting in increased release of NE (53). However, mianserin has multiple pharmacological actions, which complicate interpretations about the possible value of selective a-2 adrenoceptor antagonists in the treatment of depression.
The probable existence of a-2 adrenoceptor subtypes continues to receive considerable attention, and a-2a and a-2b adrenoceptors have been proposed based upon radioligand binding studies (54). Moreover, Regan and colleagues have demonstrated the existence of multiple genes which encode for a-2 adrenoceptors (55). These a-2 adrenoceptor subtypes may mediate functionally distinct processes; for example, a-2a, but not a-2b, adrenoceptor antagonists appear to block a adrenoceptor-mediatedinhibition of insulin release in the rat pancreas (56,57). The design of highly selective compounds which will assist in the elucidation of these purported a-adrenoceptor subtypes continues to be a formidable objective. The imidazoline derivative, idazoxan (14).is the prototypic a-2 antagonist. It has served as a template for much of the recent a-2 antagonist medicinal chemistry. The SAR of a series of tetrahydroisoquinolinylimidazolines related to idazoxan was reported (58). In this series, some derivatives were found to be modestly selective as antagonists of ['HIidazoxan labeled sites, whereas some had selectivity as antagonists of ['HI-yohimbine labeled sites in brain tissue. On the basis of radioligand binding studies, the 8-chloro derivative fi demonstrated a 7-fold selectivity for a-2 versus a-1 adrenoceptors. Moreover,
4
"1
L4
R=H 17 R = Ph
HuX O
-
the compound displayed 36-fold selectivity as an antagonist of [)H]-idazoxan-versus ['HIyohimbine-labeled a-2 adrenoceptors. As determined by functional studies in the guinea pig ileum, the compound was a partial agonist at a-2 adrenoceptors (58). Benzodioxane derivatives may function as antagonists at either a-2 or a-1 adrenoceptors (e.g., idazoxan or WB 4101 U), respectively). Compound fl,the analogue of 16 in which a trans phenyl group has been placed at position 3 of the dioxane ring, is substantially more selective than 16 for a-1 adrenoceptors. This was primarily the result of a phenyl-induced reduction in affinity for a-2 receptors, presumably due to a sterically deleterious interactions of the phenyl moiety with the a-2 receptor (59). The selectivity ratios of 16 and 12 for a- 1 versus a-2 receptors were 794 and 23442, respectively. The imidazole derivative is a potent antagonist of a-2 adrenoreceptors, with a pA2 of 8.73 versus clonidine-induced inhibition of electrically simulated contractions of the guinea pig ileum. Importantly the a2/a- 1 adrenoceptor selectivity ratio was 8 1. Finally, the compound was also reported to be a weak inhibitor of the presynaptic NE transporter; by promoting the release of NE and blocking its reuptake, such a compound would be expected to enhance noradrenergic
Chap. 3
Antidepressants
Robertson. Fuller 27
function markedly (60). Napamezole (U) has been previously described as an a - 2 adrenoceptor antagonist with modest selectivity for a-2 versus a- 1 adrenoceptors. Full reports on the in virro (61) and in vivo (62) pharmacology of napamezole were recently published; in vitro studies demonstrated that napamezole weakly inhibits 5HT reuptake. However, in vivo, the compound appeared to block a-2 adrenoceptors and inhibit 5HT uptake at comparable doses, suggesting that the compound could affect two key neurotransmitters simultaneously. The tetracyclic compound 2Q is a structural hybrid between rauwolscine and the previously reported a-2 adrenoceptor antagonist W Y 26703 (2L). The 8aR,12aS,13aS isomer is over three orders of magnitude more potent than its optical antipode, and the a-2/a-l selectivity ratio of the compound is in excess of 15000 (63,64).
H
L8
21
L9
2 Q
22
Compound 22,a structural hybrid of reboxetine and idazoxan, was synthesized to combine the NE uptake-inhibiting properties of the former drug and the a-2 adrenoreceptor blocking properties of the latter drug. Unfortunately, 22 and several analogs were not active either as a-2 receptor antagonists or as norepinephrine uptake inhibitors (65). 5HTla Agonists - A general discussion of the medicinal chemistry of 5HTla agonists can be found in Chapter 11 of this volume (66). Recent clinical studies have found that buspirone, gepirone, and ipsapirone are effective antidepressants (67-72). These compounds appear to exert their anxiolytic effects by their actions as 5HTla partial agonists; moreover, it has been suggested that the same molecular action accounts for their more recently discovered antidepressant activities. However, an alternative mechanism for their antidepressant actions has been proposed. These compounds are metabolized extensively (73,74)to 1-(2-pyrimidinyl)piperazine (1-PP). This metabolite has little affinity for 5HT receptors (73), and it is not thought to be involved in the anxiolytic effects produced by administration of the parent drug (75). However, based upon its pharmacological actions, the metabolite may be involved in the antidepressant actions of these structurally related 5HT1a agonists. 1-PP is a relatively potent a-2 adrenoceptor antagonist (73,7678). In blood and brain of animals treated with buspirone or gepirone, 1-PP levels were higher and persisted longer than parent drug (73). In blood of humans treated with buspirone, the metabolite I-PP is present at markedly higher concentrations than buspirone (73). In vivo blockade of a-2 adrenoceptors occurs after buspirone or gepirone administration, due to the formation and persistence of the metabolite 1-PP (76,7942). As described in a previous section of this
Section I-CNS Agents
28
McCall. Ed
chapter, a variety of a-2adrenoceptor antagonists are under development for the treatment of depression (83). Thus the pharmacological actions of the metabolite 1-PP complicates mechanistic interpretations relative to the antidepressant effects of presently available SHT1a partial agonists. Further studies with additional SHTla receptor agonists, particularly with agonists of other structural types that do not liberate pharmacologically active substances, should clarify the mechanisms involved in the antidepressant actions of these drugs. Some animal studies support the hypothesis that SHTla receptor agonists have (8intrinsic antidepressant effects. For example, 8-hydroxy-2-(di-N-propylamino)tetralin OH-DPAT, 24), a prototypic full agonist at 5HTla receptors, was active in a learned helplessness behavior paradigm in rats (84).This model is often considered to be predictive of clinical antidepressant activity. 8-OH-DPAT, as well as piperazine-derived SHTla partial agonists, reduced immobility time in the forced swim test in rats (85). These behavioral studies with SHTla receptor agonists in rats support earlier findings (86,87).The 8methylthio analog (2) of 8-OH-DPAT was reported to be more potent than 8-OH-DPAT itself (88). The 5-fluoro derivative (26) of 8-OH-DPAT was reported to be a relatively impotent antagonist of SHTla receptors (89).
5"'
X
24 X = O H , Y = H
a
22 28
X=SCH3,Y=H X=OH,Y=F
x=4 x=2
The benzodioxane derivative MDL 72832 (2T,has been previously reported to be a partial agonist at SHTla receptors (90). In a variety of assays, the eudismic ratio was approximately 32, and the levorotatory isomer was the more potent enantiomer (90,91).A is also a potent SHTla partial agonist homologue of this compound, MDL 73005EF and is active in animal models of anxiety (92). Structural modification of the a-2 adrenoceptor antagonist (SKF 86466) resulted in 3, which had relatively high and balanced affinities for both a-2 and SHTla receptors (pKi values were 8.1 and 7.6, respectively (93).In addition to SHTla agonists, preliminary clinical trials suggest that the SHT2 receptor antagonists ritanserin (94)and nefazodone (95)may have clinical efficacy in the treatment of depression.
(a,
a
N-CH, CI
Cl
29
24
Other mechanistic approaches - Inhibitors of M A 0 have been used for more than 30 years in the treatment of depression. Because of potentially lethal hypertensive crises following ingestion of foods containing sympathomimetic amines, MA0 inhibitors are used relatively infrequently in the treatment of major depression (96). However, M A 0 inhibitors currently used to treat depression in the U.S. are irreversible inhibitors, and are relatively nonselective a reversible inhibitor for the two isozymes of MAO, type A and type B. Moclobemide highly selective for type A MAO, was recently introduced to the marketplace in some countries (97). Other selective and reversible MAO-A inhibitors, including brofdromine
u,
Antidepressants
Chap 3
Robertson, Fuller 29
(m,
are under development (98). The fact that these compounds appear to be effective antidepressants, without the risk of severe cardiovascular side effects that plague the older MA0 inhibitors, may lead to a more widespread utilization of MA0 inhibitors (99).
Rolipram (s)is a prototypic inhibitor of the type IV, cGMP-insensitive phosphodiesterase (PDE), an isoform of phosphodiesterase that appears to be particularly important in modulating CAMP metabolism in the CNS (100-102). Rolipram has demonstrated antidepressant efficacy in over 14 double-blind clinical mals (103- 105). An SAR study of rolipram, and a topographical model of its binding site on the phosphodiesterase isozyme, were presented (106). For a wide range of rolipram analogues, there were highly significant correlations between the potencies of compounds to antagonize reserpine-induced hypothermia in mice or induce head twitches in rats, and their potencies as antagonists of [3H]-rolipram binding ex vivo (107). These data, when coupled with the strong evidence that [3H]-rolipram binds specifically to the PDE isozyme, lend further support to the hypothesis that the behavioral effects of rolipram are mediated by inhibition of type IV,cGMP-insensitive PDE (108).
6, 33
34
33
MDL 26,479 (3) does not inhibit monoamine uptake camers in vitro, but it does antagonize Ro 4- 1284 induced hypothermia and reserpine-induced ptosis in mice, effects usually seen with potent monoamine uptake inhibitors (109). When given chronically, both and desipramine attenuated NE enhancement of inhibitory responses to GABA on Purkinje neurons. Unlike desipramine, acute treatment with 3decreased noradrenergic enhancement of GABA inhibition, suggesting 3might have a faster onset of antidepressant action clinically (109). Based upon animal studies, substances that reduce neurotransmission at the NMDA (N-methyl-D-aspartate) receptor complex (1 10) may represent a new class of antidepressant drugs. A variety of NMDA modulators mimicked the effects of antidepressant drugs in reducing the duration of immobility in a forced-swim test in mice, including 2-amino-7phosphonoheptanoic acid (AP-7), a competitive NMDA receptor antagonist; dizolcipine (MK-801), a noncompetitive NMDA receptor antagonist; and 1-aminocyclopropanecarboxylic acid, a partial agonist at strychnine-insensitive glycine receptors (1 11). A series reduced immobility in Porsolt’s behavioral of 4-amino-[ 1,2,4]-triazolo-[4,3-a]-quinoxalines despair model in rats, a preclinical model designed to detect antidepressants (1 12). These compounds were potent adenosine A1 and A2 receptor antagonists, and this was presumed to be the biochemical mechanism of their behavioral effects; X was one of the optimal compounds (1 12). Captopril exhibited activity comparable to imipramine in the learned helplessness paradigm in rats (1 13). Moreover, a variety of anecdotal clinical reports
30
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suggest that captopril exhibits mood-elevating and antidepressant properties in man (114). Determination of whether ACE inhibitors, or the newly developed angiotensin I1 receptor antagonists (115), can be used to treat affective disorders will require carefully controlled, prospective clinical trials. Conclusions - The decade of the 1990s will witness the introduction of a wide variety of additional antidepressant drugs. Many of these compounds will be advances in that they will produce fewer side effects than tricyclic antidepressants. However, development of compounds which produce therapeutic effects more rapidly, or in greater percentage of patients, than tricyclic antidepressantsremain elusive goals. Discovery of such compounds will probably require a more sophisticated understanding of the fundamental biochemical aberrations which underlie depression. Feferenca 1.
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