- Dibenzo[b,f][1,4]oxazepines and dibenzo[b,e]oxepines: Influence of the chlorine substitution pattern on the pharmacology at the H1R, H4R, 5-HT2AR and other selected GPCRs
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Inspired by VUF6884 (7-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine), reported as a dual H1/H4 receptor ligand (pKi: 8.11 (human H1R (hH1R)), 7.55 (human H4R (hH4R))), four known and 28 new oxazepine and related oxepine derivatives were synthesised and pharmacologically characterized at histamine receptors and selected aminergic GPCRs. In contrast to the oxazepine series, within the oxepine series, the new compounds showed high affinity to the hH1R (pKi: 6.8–8.7), but no or moderate affinity to the hH4R (pKi: ≤ 5.3). For one oxepine derivative (1-(2-Chloro-6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4-methylpiperazine), the enantiomers were separated and the R-enantiomer was identified as the eutomer at the hH1R (pKi: 8.83 (R), 7.63 (S)) and the guinea-pig H1R (gpH1R) (pKi: 8.82 (R), 7.41 (S)). Molecular dynamic studies suggest that the tricyclic core of the compounds is bound in a similar mode into the binding pocket, as described for doxepine in the hH1R crystal structure. Moreover, docking studies of all oxepine derivatives at the hH1R indicate that the oxygen and the position of the chlorine in the tricyclic core determines, if the R- or the S-enantiomer is the eutomer. For some of the oxazepines and oxepines the affinity to other aminergic GPCRs is in the same range as to hH1R or hH4R, thus, those compounds have to be classified as dirty drugs. However, one oxazepine derivative (3,7-Dichloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine was identified as dual hH1/h5-HT2A receptor ligand (pKi: 9.23 (hH1R), 8.74 (h5-HT2AR), ≤7 at other analysed GPCRs), whereas one oxepine derivative (1-(3,8-Dichloro-6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4-methylpiperazine) was identified as selective hH1R antagonist (pKi: 8.44 (hH1R), ≤6.7 at other analyzed GPCRs). Thus, the pharmacological results suggest that the oxazepine/oxepine moiety and additionally the chlorine substitution pattern toggles receptor selectivity and specificity.
- Naporra, Franziska,Gobleder, Susanne,Wittmann, Hans-Joachim,Spindler, Julia,Bodensteiner, Michael,Bernhardt, Günther,Hübner, Harald,Gmeiner, Peter,Elz, Sigurd,Strasser, Andrea
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p. 610 - 625
(2016/10/12)
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- AMINO SUBSTITUTED DIARYL[A,D]CYCLOHEPTENE ANALOGS AS MUSCARINIC AGONISTS AND METHODS OF TREATMENT OF NEUROPSYCHIATRIC DISORDERS
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Disclosed herein are analogs of clozapine and pharmaceutically acceptable salts, esters, amides, or prodrugs thereof; methods of synthesizing the analogs; and methods of using the analogs for treating neuorpsychiatric disorders. In some embodiments, the analogs are amino substituted diaryl[a,d]cycloheptenes.
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Page/Page column 79
(2008/06/13)
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- Synthesis and evaluation of antipsychotic activity of 11-(4-aryl-1- piperazinyl)-dibenz [b, f][1,4] oxazepines and their 8-chloro analogues
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Atypical drugs reduce positive and negative symptoms of schizophrenia, without inducing EPS, but they exert other undesirable side effects. We have gone for synthesis of novel derivatives of Loxapine which are devoid of catalepsy and have decreased metabolic demethylation which is the prominent factor for bioavailability of the drug. While doing so we have also been successful in retaining the antipsychotic activity of the drug. Condensation of 8,11-dichlorodibenzoxazepine and 11-chlorodibenzoxazepine with 1-aryl piperazines was carried to give 8-chloro-11-(4-aryl-1-piperazinyl)-dibenz[b,f] [1,4]oxazepines and 11-(4-aryl-1-piperazinyl)-dibenz[b,f][1,4]oxazepines respectively. These derivatives were found as active as Clozapine.
- Wagh,Patil,Jain,Harak,Wagh
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p. 165 - 172
(2008/02/12)
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- Loxapine analogs and methods of use thereof
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The invention relates to novel compounds and methods of using them for modulating sleep.
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Page/Page column 75-76
(2008/06/13)
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- USE OF N-DESMETHYLCLOZAPINE AND RELATED COMPOUNDS AS DOPAMINE STABILIZING AGENTS
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Disclosed herein is the use of N-desmethylclozapine (NDMC) and related compounds to treat a variety of neuropsychiatric diseases including psychosis. It is shown that NDMC and related compounds are agonists or partial agonists at D2 and D3 dopamine receptors and thus may be effective as a dopamine stabilizing agent, allowing it to be used to treat or provide reduced incidence of Extrapyramidal symptoms (EPS) and/or tardive dyskinesias (TD). Also disclosed is administering NDMC and related compounds in combination with other anti-psychotic agents.
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Page/Page column 95
(2010/11/24)
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- AMINO SUBSTITUTED DIARYL[A,D]CYCLOHEPTENE ANALOGS AS MUSCARINIC AGONISTS AND METHODS OF TREATMENT OF NEUROPSYCHIATRIC DISORDERS
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Disclosed herein are analogs of clozapine and pharmaceutically acceptable salts, esters, amides, or prodrugs thereof; methods of synthesizing the analogs; and methods of using the analogs for treating neuorpsychiatric disorders. In some embodiments, the analogs are amino substituted diaryl[a,d]cycloheptenes.
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Page/Page column 76
(2008/06/13)
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- ALKYL-SUBSTITUTED COMPOUNDS HAVING DOPAMINE RECEPTOR AFFINITY
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Described herein are D4 receptor-selective compounds of the general formula: STR1 wherein: A and B are independently selected, optionally substituted, unsaturated 5-or 6-membered, homo-or heterocyclic rings; X 1 is selected from CH 2, O, NH, S, C. dbd.O, CH--OH, CH--N(C 1-4 alkyl) 2, C=CHCl, C=CHCN, N--C 1-4 alkyl, N-acetyl, SO 2 and SO;X 2---is selected from N=, CH 2--, CH= and C(O);Y is selected from N and CH;R. sub.1 represents C 1-4 alkyl;n is 0, 1 or 2;q is 1 or 2; andZ is C 5-10 alkyl optionally substituted with OH, halo, C 1-4 alkyl or C 1-4 alkoxy and optionally incorporating a heteroatom selected from O, N and S;and acid addition salts, solvates and hydrates thereof. Their use as ligands for dopamine receptor identification and in a drug screening program, and as pharmaceuticals to treat indications in which D4 receptor stimulation is implicated, such as schizophrenia, is also described.
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- ALKYL-SUBSTITUTED COMPOUNDS HAVING DOPAMINE RECEPTOR AFFINITY
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Described herein are D4 receptor-selective compounds of the general formula: STR1 wherein: A and B are independently selected, optionally substituted, saturated or unsaturated 5-or 6-membered, homo-or heterocyclic rings;X 1 is selected from CH 2, O, NH, S, C=O, CH--OH, CH--N(C 1-4 alkyl) 2, C=CHCl, C= CHCN, N--C 1-4 alkyl, N-acetyl, SO 2 and SO;X. sub.2 . . . is selected from N=, CH 2--, CH=, C(O)--, O--, and S--;Y is selected from N and CH; R. sub.1 represents C 1-4 alkyl;n is 0, 1 or 2;q is 1 or 2; andZ is C 5-10 alkyl optionally substituted with OH, halo, C 1-4 alkyl or C 1-4 alkoxy and optionally incorporating a heteroatom selected from O, N and S; and acid addition salts, solvates and hydrates thereof. Their use as ligands for dopamine receptor identification and in a drug screening program, and as pharmaceuticals to treat indications in which the D4 receptor is implicated, such as schizophrenia, is also described.
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