Differential Effects of a New Dibenzo-Epine Neuroleptic Compared with Haloperidol Results of an Open and Crossover Study

Mann, Klaus; Bartels, M.; Hj, Gärtner; Hw, Schied; Wagner, Willi L.; Heimann, H

doi:10.1055/s-2007-1017094

Cited by 16 publications

(3 citation statements)

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“…Like clozapine, it has high relative affinity for 5HT2a receptors [83]. It is an effective anti-psychotic agent with low incidence of motor side effects [28,37,72,129,130], and is also effective against drug-induced psychosis in Parkinson’s disease [62,105]. Its efficacy in refractory psychosis is not proven, but is suggested by one clinical trial [37], whose patient group included ten patients in this class, and for which overall results were “better than previous drugs” in 60% of patients (similar to clozapine).…”

Section: Are There Any Other Drugs In Regular Use With Properties LImentioning

confidence: 99%

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Mechanisms of Action of Antipsychotic Drugs of Different Classes, Refractoriness to Therapeutic Effects of Classical Neuroleptics, and Individual Variation in Sensitivity to their Actions: PART II

Miller

2009

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Rapid-onset psychotic rebound is uncommon on discontinuation of most antipsychotic drugs, as might be expected for antipsychotic drugs with (hypothetically) indirect actions at their final target receptors. Rapid-onset psychosis is more common on withdrawal of clozapine, which might be expected if its action is direct. Drugs other than clozapine (notably thioridazine) may have hitherto unrecognised similarities to clozapine (but without danger of agranulocytosis), and may be useful in treatment of refractory psychosis. Quetiapine fulfils only some criteria for a clozapine-like drug. Clinical response to neuroleptics varies widely at any given plasma level. Haase’s “neuroleptic threshold” concept suggests that the dose producing the slightest motor side effects produces most or all of the therapeutic benefit, but analyses presented here suggest that antipsychotic actions are not subject to a sharp “all-or-none” threshold but increase over a small dose range. This concept could provide a method for quantitative determination of individualized optimal doses.

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Section: Are There Any Other Drugs In Regular Use With Properties LImentioning

confidence: 99%

“…(✓):suggestive evidence that criterion is fulfilled.Sources:a:[28,37,72,129,130];b:[43,124];c:[32];d:[19,49,56];e:[37];f:[17,51,67,124];g:[18,79,116];h:[83];i:[12,100,134];j:see Table 1 (PART I)k:[62,105]:l:[55];m:[26,29,35,40,54,60,92];n:[7,23,30,68,111];o:[36]. …”

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confidence: 99%

Mechanisms of Action of Antipsychotic Drugs of Different Classes, Refractoriness to Therapeutic Effects of Classical Neuroleptics, and Individual Variation in Sensitivity to their Actions: PART II

Miller

2009

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“…Development of fluperlapine (NB-106-689, 2) had to be abandoned because clinical trials revealed some cases of agranulocytosis. 4 The thiophene analogue, tilozepine (NT 104-252, 3), showed promising properties as an antipsychotic agent, but clinical trials had to be discontinued because 3 produced epileptiform seizures.5 Flumezapine (LY 120363, 4), another thiophene isostere of clozapine, was found to be a potent blocker of the dopamine D-2 and serotonin S-2 receptors,6 but further development has not been reported. Further, in the 4-methyl-4H-thieno [3,46] analogue (5) of clozapine, the cataleptogenic properties (2) 192 ± 37 (5) 2770 ± 380 (7) lb6 39 ± 11 (2) 895 ± 704 (2) >10000 (2) lc6 55 ± 18 (2) 63 ± 17 (2) 218 ± 28 (…”

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Chloro-substituted, sterically hindered 5,11-dicarbo analogs of clozapine as potential chiral antipsychotic agents

Davis¹,

Janowsky²,

Smith³

1990

J. Med. Chem.

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Variable-temperature proton nuclear magnetic resonance studies have shown that 5-(2-propylidene)-10-(4-methylpiperazino)-5H-dibenzo[a,d] cycloheptene, a 5,11-dicarbo analogue of the atypical neuroleptic agent clozapine [8-chloro-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]diazepine], exists as thermally stable configurational isomers. The presence of the 2-propylidene group at C-5 on the 5H-dibenzo[a,d]cycloheptene moiety did not interfere greatly, as compared to clozapine, with the in vitro affinity of this 5,11-dicarbo analogue of clozapine for muscarinic and dopamine D-1 and D-2 binding sites in rat brain. Since the presence and position of a chloro substituent on the 5H-dibenzo[b,e][1,4]diazepine moiety have a marked influence on the respective binding affinities of 1,4-diazepines related to clozapine, chloro-substituted 5,11-dicarbo analogues of clozapine were prepared in order to further examine structure-activity relationships. Evaluation of these analogues for binding to muscarinic and dopamine binding sites in comparison with clozapine and other 5H-dibenzo[b,e][1,4]diazepine analogues of clozapine shows that the dopamine D-1 and D-2 receptor affinities of both the 5-(2-propylidene)-5,11-dicarbo analogue and its corresponding distal-chloro derivative, 2-chloro-5-(2-propylidene)-10-(4-methylpiperazino)-5H- dibenzo[a,d]cycloheptene, are retained. Because of the susceptibility to acid-catalyzed hydrolysis of these tertiary enamines, however, these compounds serve only as model compounds for their structure-activity evaluation. Since the proximal nitrogen atom of the piperazine ring is redundant for biological activity, 5-(2-propylidene)-10-(1-methyl-4-pyridyl)-5H-dibenzo[a,d]cycloh eptene and its 2-chloro derivative are excellent candidates for resolution into enantiomers as a means to separate antimuscarinic and antidopaminergic activity, respectively, associated with only a single stereoisomer.

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Minimizing the Potential for Drug Bioactivation of Drug Candidates to Success in Clinical Development

Nassar

2008

Drug Metabolism Handbook

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Differential Effects of a New Dibenzo-Epine Neuroleptic Compared with Haloperidol Results of an Open and Crossover Study

Cited by 16 publications

References 0 publications

Mechanisms of Action of Antipsychotic Drugs of Different Classes, Refractoriness to Therapeutic Effects of Classical Neuroleptics, and Individual Variation in Sensitivity to their Actions: PART II

Mechanisms of Action of Antipsychotic Drugs of Different Classes, Refractoriness to Therapeutic Effects of Classical Neuroleptics, and Individual Variation in Sensitivity to their Actions: PART II

Chloro-substituted, sterically hindered 5,11-dicarbo analogs of clozapine as potential chiral antipsychotic agents

Minimizing the Potential for Drug Bioactivation of Drug Candidates to Success in Clinical Development

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