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Kjell Svensson - One of the best experts on this subject based on the ideXlab platform.
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dopamine agonist induced yawning in rats a dopamine D3 receptor mediated behavior
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Gregory T. Collins, Amy Hauck Newman, Peter Grundt, Jeffrey M Witkin, Kjell Svensson, James H. WoodsAbstract:A specific role for the dopamine D3 receptor in behavior has yet to be elucidated. We now report that dopamine D2/D3 agonists elicit dose-dependent yawning behavior in rats, resulting in an inverted U-shaped dose-response curve. A series of experiments was directed toward the hypothesis that the induction of yawning is a D3 receptor-mediated effect, whereas the inhibition of the yawning observed at higher doses is due to competing D2 receptor activity. We compared several dopaminergic agonists with a range of in vitro D3 selectivity, including PD-128,907 [( S )-(+)-(4 aR , 10 bR )-3,4,4 a ,10 b -tetrahydro-4-propyl-2 H ,5 H -[1]benzopyrano-[4,3- b ]-1,4-oxazin-9-ol HCl], PD-128,908 [( R )-(-)-(4 aS ,10 bS )-3,4,4 a ,10 b -tetrahydro-4-propyl-2 H ,5 H -[1]benzopyrano-[4,3- b ]-1,4-oxazin-9-ol HCl], quinelorane [(5 aR - trans )-5,5 a ,6,7,8, 9,9 a ,10-octahydro-6-propylpyrido[2,3- g ]quinazolin-2-amine dihydrochloride], pramipexole ( N ′-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine), 7-OH-DPAT [(±)-7-hydroxy-2-dipropylaminotetralin HBr], quinpirole [ trans -(-)-(4 aR )-4,4 a ,5,6,7,8, 8 a ,9-octahydro-5-propyl-1 H -pyrazolo[3,4- g ]quinoline HCl], bromocriptine [(+)-2-bromo-12′-hydroxy-2′-(1-methylethyl)-5′-(2-methylpropyl) ergotaman-3′,6′-18-trione methanesulfonate], and apomorphine [( R )-(-)-5,6,6 a ,7-tetrahydro-6-methyl-4 H -dibenzo-[ de , g ]quinoline-10,11-diol HCl] with respect to their ability to induce yawning in rats. A series of D2/D3 Antagonists differing in selectivity for D3 over D2 receptors were evaluated for their ability to alter the effects of the dopamine agonists. The Antagonists L-741,626 (3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1 H -indole), haloperidol (4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone HCl), nafadotride ( N -[(1-butyl-2-pyrrolidinyl)methyl]-4-cyano-1-methoxy-2-naphtha-lenecarboxamide), U99194 (2,3-dihydro-5,6-dimethoxy- N , N -dipropyl-1 H -inden-2-amine maleate), SB-277011A ( trans - N -[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide), and PG01037 ( N -{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]- trans -but-2-enyl}-4-pyridine-2-yl-benzamide HCl) were used to determine effects on dose-response curves for D2/D3 agonist-induced yawning. In addition, the potential contribution of cholinergic and/or serotonergic mechanisms to the yawning response was investigated using a series of pharmacological tools including scopolamine [( a ,S)- a -(hydroxymethyl)benzeneacetic acid (1 a ,2 b ,4 b, 5 a ,7 b )-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]-non7-yl ester hydrobromide], mianserin (1,2,3,4,10,14 b -hexahydro-2-methyldibenzo[ c , f ]pyrazino[1,2- a ]azepine HCl), and the D3-preferring Antagonists nafadotride, U99194, SB-277011A, and PG01037 to differentially modulate yawning induced by PD-128,907, physostigmine [(3 aS )- cis -1,2,3,3 a ,8,8 a -hexahydro-1,3 a ,8-trimethylpyrrolo[2,3- b ]indol-5-ol methylcarbamate hemisulfate], and N -[3-(trifluoromethyl)phenyl]piperazine HCl. The results of these experiments provide convergent evidence that dopamine D2/D3 agonist-induced yawning is a D3 agonist-mediated behavior, with subsequent inhibition of yawning being driven by competing D2 agonist activity. Thus, dopamine agonist-induced yawning may represent an in vivo method for selectively identifying D3 and D2 receptor-mediated activities.
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Dopamine D3 Receptor Antagonists. 1. Synthesis and Structure−Activity Relationships of 5,6-Dimethoxy-N-alkyl- and N-Alkylaryl-Substituted 2-Aminoindans
Journal of medicinal chemistry, 2001Co-Authors: Susanne R. Haadsma-svensson, Kerry Anne Cleek, Dac M. Dinh, J. Neil Duncan, Christopher L. Haber, Rita M. Huff, Mary E. Lajiness, Nanette F. Nichols, Martin W. Smith, Kjell SvenssonAbstract:5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D3 receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure−activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D3 Antagonists. Thus, combinations of various alkyl groups were generally inactive at the D3 receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D3 binding affinity, the D2 affinity is also enhanced, resulting in a less than 4-fold preference for the D3 receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D3 antagonist 3 has been dev...
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dopamine D3 receptor Antagonists 1 synthesis and structure activity relationships of 5 6 dimethoxy n alkyl and n alkylaryl substituted 2 aminoindans
Journal of Medicinal Chemistry, 2001Co-Authors: Susanne R Haadsmasvensson, Kerry Anne Cleek, Dac M. Dinh, Christopher L. Haber, Rita M. Huff, Mary E. Lajiness, Nanette F. Nichols, Martin W. Smith, Neil J Duncan, Kjell SvenssonAbstract:5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D3 receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure−activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D3 Antagonists. Thus, combinations of various alkyl groups were generally inactive at the D3 receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D3 binding affinity, the D2 affinity is also enhanced, resulting in a less than 4-fold preference for the D3 receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D3 antagonist 3 has been dev...
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Discriminative stimulus properties of the dopamine D3 antagonist PNU-99194A
Psychopharmacology, 1998Co-Authors: S. R. Franklin, Lisa E. Baker, Kjell SvenssonAbstract:It was recently documented that the relatively selective dopamine D3 receptor antagonist, PNU-99194A, is capable of establishing discriminative stimulus control in rats and that the discriminative cue associated with this compound is not similar to that produced by psychostimulants. The present experiment further characterized the discriminative stimulus properties of PNU-99194A by examining several other dopaminergic agents for stimulus generalization in 23 male Sprague-Dawley rats trained to discriminate 10 mg/kg PNU-99194A (SC, 15 min) from vehicle in a two-choice discrimination procedure under an FR10 schedule of food reinforcement. Rats achieved a criterion of ten consecutive sessions with correct lever choice after a median of 35.5 sessions (range 23-78). In substitution tests, the non-selective D2 receptor antagonist, haloperidol (0.01- 0.1 mg/kg), and the mixed D2/D3 Antagonists, amisulpiride (3.2-32 mg/kg) and sulpiride (32-200 mg/kg), failed to produce stimulus generalization, while the D3-preferring Antagonists, (-)-DS121 (1-10 mg/kg) and (+)-AJ76 (3.2-32 mg/kg), produced complete stimulus generalization. Direct and indirect DA agonists, including apomorphine (0.01-0.32 mg/kg) and d-amphetamine (0.1-1 mg/kg), the D1 agonist SKF38393 (10-100 mg/kg), the D2 selective agonist PNU-95666E (0.32-3.2 mg/kg) and the D3-preferring agonist pramipexole (0.032-1 mg/kg), all produced non-significant amounts of drug-appropriate responding and significantly reduced response rate. It is concluded that PNU-99194A produces a distinctive subjective cue which is probably based on D3 receptor antagonism.
Seiji Nishino - One of the best experts on this subject based on the ideXlab platform.
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sulpiride a d2 D3 blocker reduces cataplexy but not rem sleep in canine narcolepsy
Neuropsychopharmacology, 2000Co-Authors: Mutsumi Okura, Joyce Riehl, Emmanuel Mignot, Seiji NishinoAbstract:Cataplexy, an abnormal manifestation of REM sleep atonia, is currently treated with antidepressants. These medications also reduce physiological REM sleep and induce nocturnal sleep disturbances. Because a recent work on canine narcolepsy suggests that the mechanisms for triggering cataplexy are different from those for REM sleep, we hypothesized that compounds which act specifically on cataplexy, but not on REM sleep, could be developed. Canine studies also suggest that the dopamine D2/D3 receptor mechanism is specifically involved in the regulation of cataplexy, but little evidence suggests that this mechanism is important for REM sleep regulation. We therefore assessed the effects of sulpiride, a commonly used D2/D3 antagonist, on cataplexy and sleep in narcoleptic canines to explore the possible clinical application of D2/D3 Antagonists for the treatment of human narcolepsy. Both acute and chronic oral administration of sulpiride (300 mg/dog, 600 mg/dog) significantly reduced cataplexy without noticeable side effects. Interestingly, the anticataplectic dose of sulpiride did not significantly reduce the amount of REM sleep. Sulpiride (and other D2/D3 Antagonists) may therefore be an attractive new therapeutic indication in human narcolepsy.
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Sulpiride, a D2/D3 Blocker, Reduces Cataplexy but not REM Sleep in Canine Narcolepsy
Neuropsychopharmacology, 2000Co-Authors: Mutsumi Okura, Joyce Riehl, Emmanuel Mignot, Seiji NishinoAbstract:Cataplexy, an abnormal manifestation of REM sleep atonia, is currently treated with antidepressants. These medications also reduce physiological REM sleep and induce nocturnal sleep disturbances. Because a recent work on canine narcolepsy suggests that the mechanisms for triggering cataplexy are different from those for REM sleep, we hypothesized that compounds which act specifically on cataplexy, but not on REM sleep, could be developed. Canine studies also suggest that the dopamine D2/D3 receptor mechanism is specifically involved in the regulation of cataplexy, but little evidence suggests that this mechanism is important for REM sleep regulation. We therefore assessed the effects of sulpiride, a commonly used D2/D3 antagonist, on cataplexy and sleep in narcoleptic canines to explore the possible clinical application of D2/D3 Antagonists for the treatment of human narcolepsy. Both acute and chronic oral administration of sulpiride (300 mg/dog, 600 mg/dog) significantly reduced cataplexy without noticeable side effects. Interestingly, the anticataplectic dose of sulpiride did not significantly reduce the amount of REM sleep. Sulpiride (and other D2/D3 Antagonists) may therefore be an attractive new therapeutic indication in human narcolepsy.
Masatoshi Tanaka - One of the best experts on this subject based on the ideXlab platform.
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Dopamine D3 Receptors Modulate Evoked Dopamine Release from Slices of Rat Nucleus Accumbens Via Muscarinic Receptors, But Not from the Striatum
2016Co-Authors: Shigeto Yamada, Mutsuo Harano, Naoko Annoh, Masatoshi TanakaAbstract:It is not clear whether dopamine D3 receptor contributes to the regional difference in dopamine antagonist-induced increase in the evoked dopamine release from the nucleus accumbens and striatum. We investigated the regional differences in augmen-tation of electrically evoked dopamine release induced by pref-erential dopamine D2 or D3 receptor Antagonists from slices of the rat striatum and nucleus accumbens. Haloperidol, a pref-erential dopamine D2 receptor antagonist, enhanced the evoked dopamine release from both the striatum and nucleus accumbens. Preferential dopamine D3 Antagonists, cis-(1)-(1S,2R)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin HCl [(1)-UH232] and 5,6-dimethoxy-2-(di-n-propylamine)indan (U-99194A) resulted in a greater increase in the evoked dopamine released from the nucleus accumbens compared with that from the striatum. Moreover, U-99194A attenuated the quinpirole-induced reduction of evoked dopamine release from the nu-cleus accumbens but not from the striatum. When slices were superfused with pirenzepine, a muscarinic receptor antagonist, the increase in the evoked dopamine release by (1)-UH232 or U-99194A was reduced in the nucleus accumbens to the same level as that in the striatum. Our results indicate that the pref-erential D3 receptor Antagonists-induced increase in evoked dopamine release is probably mediated by the cholinergic sys-tem in the nucleus accumbens, which contains more postsyn-aptic dopamine D3 receptors than the striatum. There is substantial evidence for regional differences be-tween the striatum and nucleus accumbens with regard to dopamine metabolism and/or the activity of dopamine neu-rons induced by dopamine receptor Antagonists (Anden an
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Dopamine D3 Receptors Modulate Evoked Dopamine Release from Slices of Rat Nucleus Accumbens Via Muscarinic Receptors, But Not from the Striatum
The Journal of pharmacology and experimental therapeutics, 1999Co-Authors: Shigeto Yamada, Mutsuo Harano, Naoko Annoh, Masatoshi TanakaAbstract:It is not clear whether dopamine D3 receptor contributes to the regional difference in dopamine antagonist-induced increase in the evoked dopamine release from the nucleus accumbens and striatum. We investigated the regional differences in augmentation of electrically evoked dopamine release induced by preferential dopamine D2 or D3 receptor Antagonists from slices of the rat striatum and nucleus accumbens. Haloperidol, a preferential dopamine D2 receptor antagonist, enhanced the evoked dopamine release from both the striatum and nucleus accumbens. Preferential dopamine D3 Antagonists, cis -(+)-(1 S ,2 R )-5-methoxy-1-methyl-2-(di- n -propylamino)tetralin HCl [(+)-UH232] and 5,6-dimethoxy-2-(di- n -propylamine)indan (U-99194A) resulted in a greater increase in the evoked dopamine released from the nucleus accumbens compared with that from the striatum. Moreover, U-99194A attenuated the quinpirole-induced reduction of evoked dopamine release from the nucleus accumbens but not from the striatum. When slices were superfused with pirenzepine, a muscarinic receptor antagonist, the increase in the evoked dopamine release by (+)-UH232 or U-99194A was reduced in the nucleus accumbens to the same level as that in the striatum. Our results indicate that the preferential D3 receptor Antagonists-induced increase in evoked dopamine release is probably mediated by the cholinergic system in the nucleus accumbens, which contains more postsynaptic dopamine D3receptors than the striatum.
Mutsumi Okura - One of the best experts on this subject based on the ideXlab platform.
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sulpiride a d2 D3 blocker reduces cataplexy but not rem sleep in canine narcolepsy
Neuropsychopharmacology, 2000Co-Authors: Mutsumi Okura, Joyce Riehl, Emmanuel Mignot, Seiji NishinoAbstract:Cataplexy, an abnormal manifestation of REM sleep atonia, is currently treated with antidepressants. These medications also reduce physiological REM sleep and induce nocturnal sleep disturbances. Because a recent work on canine narcolepsy suggests that the mechanisms for triggering cataplexy are different from those for REM sleep, we hypothesized that compounds which act specifically on cataplexy, but not on REM sleep, could be developed. Canine studies also suggest that the dopamine D2/D3 receptor mechanism is specifically involved in the regulation of cataplexy, but little evidence suggests that this mechanism is important for REM sleep regulation. We therefore assessed the effects of sulpiride, a commonly used D2/D3 antagonist, on cataplexy and sleep in narcoleptic canines to explore the possible clinical application of D2/D3 Antagonists for the treatment of human narcolepsy. Both acute and chronic oral administration of sulpiride (300 mg/dog, 600 mg/dog) significantly reduced cataplexy without noticeable side effects. Interestingly, the anticataplectic dose of sulpiride did not significantly reduce the amount of REM sleep. Sulpiride (and other D2/D3 Antagonists) may therefore be an attractive new therapeutic indication in human narcolepsy.
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Sulpiride, a D2/D3 Blocker, Reduces Cataplexy but not REM Sleep in Canine Narcolepsy
Neuropsychopharmacology, 2000Co-Authors: Mutsumi Okura, Joyce Riehl, Emmanuel Mignot, Seiji NishinoAbstract:Cataplexy, an abnormal manifestation of REM sleep atonia, is currently treated with antidepressants. These medications also reduce physiological REM sleep and induce nocturnal sleep disturbances. Because a recent work on canine narcolepsy suggests that the mechanisms for triggering cataplexy are different from those for REM sleep, we hypothesized that compounds which act specifically on cataplexy, but not on REM sleep, could be developed. Canine studies also suggest that the dopamine D2/D3 receptor mechanism is specifically involved in the regulation of cataplexy, but little evidence suggests that this mechanism is important for REM sleep regulation. We therefore assessed the effects of sulpiride, a commonly used D2/D3 antagonist, on cataplexy and sleep in narcoleptic canines to explore the possible clinical application of D2/D3 Antagonists for the treatment of human narcolepsy. Both acute and chronic oral administration of sulpiride (300 mg/dog, 600 mg/dog) significantly reduced cataplexy without noticeable side effects. Interestingly, the anticataplectic dose of sulpiride did not significantly reduce the amount of REM sleep. Sulpiride (and other D2/D3 Antagonists) may therefore be an attractive new therapeutic indication in human narcolepsy.
Joyce Riehl - One of the best experts on this subject based on the ideXlab platform.
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sulpiride a d2 D3 blocker reduces cataplexy but not rem sleep in canine narcolepsy
Neuropsychopharmacology, 2000Co-Authors: Mutsumi Okura, Joyce Riehl, Emmanuel Mignot, Seiji NishinoAbstract:Cataplexy, an abnormal manifestation of REM sleep atonia, is currently treated with antidepressants. These medications also reduce physiological REM sleep and induce nocturnal sleep disturbances. Because a recent work on canine narcolepsy suggests that the mechanisms for triggering cataplexy are different from those for REM sleep, we hypothesized that compounds which act specifically on cataplexy, but not on REM sleep, could be developed. Canine studies also suggest that the dopamine D2/D3 receptor mechanism is specifically involved in the regulation of cataplexy, but little evidence suggests that this mechanism is important for REM sleep regulation. We therefore assessed the effects of sulpiride, a commonly used D2/D3 antagonist, on cataplexy and sleep in narcoleptic canines to explore the possible clinical application of D2/D3 Antagonists for the treatment of human narcolepsy. Both acute and chronic oral administration of sulpiride (300 mg/dog, 600 mg/dog) significantly reduced cataplexy without noticeable side effects. Interestingly, the anticataplectic dose of sulpiride did not significantly reduce the amount of REM sleep. Sulpiride (and other D2/D3 Antagonists) may therefore be an attractive new therapeutic indication in human narcolepsy.
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Sulpiride, a D2/D3 Blocker, Reduces Cataplexy but not REM Sleep in Canine Narcolepsy
Neuropsychopharmacology, 2000Co-Authors: Mutsumi Okura, Joyce Riehl, Emmanuel Mignot, Seiji NishinoAbstract:Cataplexy, an abnormal manifestation of REM sleep atonia, is currently treated with antidepressants. These medications also reduce physiological REM sleep and induce nocturnal sleep disturbances. Because a recent work on canine narcolepsy suggests that the mechanisms for triggering cataplexy are different from those for REM sleep, we hypothesized that compounds which act specifically on cataplexy, but not on REM sleep, could be developed. Canine studies also suggest that the dopamine D2/D3 receptor mechanism is specifically involved in the regulation of cataplexy, but little evidence suggests that this mechanism is important for REM sleep regulation. We therefore assessed the effects of sulpiride, a commonly used D2/D3 antagonist, on cataplexy and sleep in narcoleptic canines to explore the possible clinical application of D2/D3 Antagonists for the treatment of human narcolepsy. Both acute and chronic oral administration of sulpiride (300 mg/dog, 600 mg/dog) significantly reduced cataplexy without noticeable side effects. Interestingly, the anticataplectic dose of sulpiride did not significantly reduce the amount of REM sleep. Sulpiride (and other D2/D3 Antagonists) may therefore be an attractive new therapeutic indication in human narcolepsy.
