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Article: Synthesis of the enantiomers of reduced haloperidol.

Jaen, J C / Caprathe, B W / Priebe, S / Wise, L D

1991 Volume 8, Issue 8, Page(s) 1002–1005

Abstract: Reduced haloperidol (RHAL) is the best known metabolite of haloperidol (HAL), having been identified in humans, rats, and guinea pigs. Since RHAL contains an asymmetric center, it can exist in two possible enantiomeric forms. However, the enantiomeric ... ...

Abstract	Reduced haloperidol (RHAL) is the best known metabolite of haloperidol (HAL), having been identified in humans, rats, and guinea pigs. Since RHAL contains an asymmetric center, it can exist in two possible enantiomeric forms. However, the enantiomeric composition of the RHAL formed from HAL in vivo has never been reported. As a first step toward the enantiomeric analysis of biological samples, we have developed an efficient and stereospecific synthesis of (+)- and (-)-RHAL from readily available commercial materials. We have also identified an enantioselective chromatographic method using a chiral HPLC stationary phase which can detect as little as 1% of either enantiomer in synthetic samples of RHAL enantiomers.
MeSH term(s)	Chromatography, High Pressure Liquid ; Haloperidol/chemical synthesis ; Oxidation-Reduction ; Stereoisomerism
Chemical Substances	Haloperidol (J6292F8L3D)
Language	English
Publishing date	1991-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	843063-9
ISSN	1573-904X ; 0724-8741 ; 0739-0742
ISSN (online)	1573-904X
ISSN	0724-8741 ; 0739-0742
DOI	10.1023/a:1015800923078
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Article: Evaluation of the effects of the enantiomers of reduced haloperidol, azaperol, and related 4-amino-1-arylbutanols on dopamine and sigma receptors.

Jaen, J C / Caprathe, B W / Pugsley, T A / Wise, L D / Akunne, H

Journal of medicinal chemistry

1993 Volume 36, Issue 24, Page(s) 3929–3936

Abstract: The enantiomers of reduced haloperidol (3a), azaperol (3b), and the related compound BMY-14802 (3c) were prepared in high optical purity. The affinity of these compounds for dopamine D2 and D3 receptors, and sigma S1 and S2 sites was determined in vitro. ...

Abstract	The enantiomers of reduced haloperidol (3a), azaperol (3b), and the related compound BMY-14802 (3c) were prepared in high optical purity. The affinity of these compounds for dopamine D2 and D3 receptors, and sigma S1 and S2 sites was determined in vitro. Both enantiomers of 3a display greatly decreased affinity for D2 and D3 receptors compared to haloperidol, although they still possess affinities in the 100-200-nM range. Both enantiomers of 3a possess potent and equal affinity for S1 sites (Ki: 1-2 nM), only slightly weaker than haloperidol (Ki: 0.33 nM). At S2 sites, (R)-(+)-3a displays similar affinity to haloperidol (Ki: 31 and 26 nM, respectively), while (S)-(-)-3a is slight more potent (Ki: 8.2 nM). The stereoselectivity profile of the enantiomers of 3b at D2 and D3 receptors is quite similar to that of 3a, (S)-(-)-3b being about 4 times more potent than its enantiomer at both receptors. (R)-(+)-3b binds preferentially to sigma S1 over S2 sites, while (S)-(-)-3b displays the opposite selectivity profile. Both enantiomers of 3c possess very weak affinity for D2 and D3 receptors. In a manner similar to the enantiomers of 3b, the affinity of (R)-(+)-3c is greater for S1 than S2 sites, while (S)-(-)-3c displays the opposite selectivity profile. Following parenteral administration of both enantiomers of 3a, dopamine synthesis and turnover in rat striatum, cortex, and mesolimbic areas were increased, in a manner similar to the effects produced by haloperidol itself. Additional studies will be required to assess with certainty whether the effects were due to the compounds themselves or simply were a consequence of the in vivo oxidation to haloperidol.
MeSH term(s)	3,4-Dihydroxyphenylacetic Acid/metabolism ; Animals ; Antipsychotic Agents/chemistry ; Antipsychotic Agents/metabolism ; Antipsychotic Agents/pharmacology ; Brain/drug effects ; Brain/metabolism ; Butanols/chemistry ; Butanols/metabolism ; Butanols/pharmacology ; CHO Cells ; Cricetinae ; Dopamine/biosynthesis ; Dopamine Antagonists ; Guinea Pigs ; Haloperidol/chemistry ; Haloperidol/metabolism ; Haloperidol/pharmacology ; Homovanillic Acid/metabolism ; Humans ; Male ; Oxidation-Reduction ; Piperazines/chemistry ; Piperazines/metabolism ; Piperazines/pharmacology ; Pyridines/chemistry ; Pyridines/metabolism ; Pyridines/pharmacology ; Pyrimidines/chemistry ; Pyrimidines/metabolism ; Pyrimidines/pharmacology ; Rats ; Receptors, Dopamine/drug effects ; Receptors, Dopamine/metabolism ; Receptors, Dopamine D2/drug effects ; Receptors, Dopamine D2/metabolism ; Receptors, Dopamine D3 ; Receptors, sigma/drug effects ; Receptors, sigma/metabolism ; Stereoisomerism
Chemical Substances	Antipsychotic Agents ; Butanols ; DRD3 protein, human ; Dopamine Antagonists ; Drd3 protein, rat ; Piperazines ; Pyridines ; Pyrimidines ; Receptors, Dopamine ; Receptors, Dopamine D2 ; Receptors, Dopamine D3 ; Receptors, sigma ; 3,4-Dihydroxyphenylacetic Acid (102-32-9) ; alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol (105565-56-8) ; azaperol (2804-05-9) ; Haloperidol (J6292F8L3D) ; Dopamine (VTD58H1Z2X) ; Homovanillic Acid (X77S6GMS36)
Language	English
Publishing date	1993-11-26
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm00076a022
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Article: Identification of a 3-hydroxylated tacrine metabolite in rat and man: metabolic profiling implications and pharmacology.

Pool, W F / Woolf, T F / Reily, M D / Caprathe, B W / Emmerling, M R / Jaen, J C

Journal of medicinal chemistry

1996 Volume 39, Issue 15, Page(s) 3014–3018

Abstract: Discrepancies in urinary metabolic profiles in rats administered tacrine (1) suggested the presence of an unidentified metabolite of 1. Chromatographic methods were developed that allowed isolation of a metabolite fraction containing both 1- ... ...

Abstract	Discrepancies in urinary metabolic profiles in rats administered tacrine (1) suggested the presence of an unidentified metabolite of 1. Chromatographic methods were developed that allowed isolation of a metabolite fraction containing both 1-hydroxytacrine (2) and an unknown metabolite from rat urine. Mass spectral analysis indicated this metabolite to be a monohydroxylated derivative, which upon two dimensional COSY NMR analysis could be assigned as 3-hydroxytacrine (4). This structural assignment was confirmed by independent synthesis of 4. Compound 4 was also identified as a human urinary metabolite of 1. Biologically, 4 was found to have in vitro human red blood cell acetylcholinesterase inhibitory activity similar to that of 2 and 4-hydroxytacrine (5) and approximately 8-fold less than that of 1. These results underscore the need to conduct rigorous structural identification studies, especially in cases where isomeric metabolites are possible, in assessing the accuracy of chromatographic profiling techniques.
MeSH term(s)	Acetylcholinesterase/blood ; Animals ; Cholinesterase Inhibitors/urine ; Chromatography, High Pressure Liquid ; Erythrocytes/enzymology ; Humans ; Hydroxylation ; Magnetic Resonance Spectroscopy ; Male ; Mass Spectrometry ; Molecular Structure ; Rats ; Tacrine/analogs & derivatives ; Tacrine/chemistry ; Tacrine/urine
Chemical Substances	3-hydroxytacrine ; Cholinesterase Inhibitors ; Tacrine (4VX7YNB537) ; Acetylcholinesterase (EC 3.1.1.7)
Language	English
Publishing date	1996-07-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm9602266
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Article: Chemical purity and mutagenicity: case study of a drug in development.

Kropko, M L / Jaen, J C / Theiss, J C / Wold, S / Caprathe, B W / Wise, L D

Mutation research

1992 Volume 281, Issue 4, Page(s) 233–238

Abstract: During a routine Ames assay of a potential antipsychotic drug candidate, the compound appeared to be a frameshift mutagen in Salmonella typhimurium strains TA98 and TA1538. Additional testing indicated the mutagenic activity was due to one or more ... ...

Abstract	During a routine Ames assay of a potential antipsychotic drug candidate, the compound appeared to be a frameshift mutagen in Salmonella typhimurium strains TA98 and TA1538. Additional testing indicated the mutagenic activity was due to one or more contaminants incurred during synthesis. While the compound was initially shown to be greater than 98% pure by high-performance liquid chromatography, the presence of small amounts (0.01-0.1%) of a highly mutagenic impurity produced positive mutagenicity results. The need to assess for chemical purity before discontinuing development of drug candidates found positive in the Ames assay is discussed.
MeSH term(s)	Aminoquinolines/isolation & purification ; Aminoquinolines/toxicity ; Drug Contamination ; Drug Evaluation, Preclinical ; Mutagenicity Tests/standards ; Mutagens/isolation & purification ; Mutagens/toxicity ; Salmonella typhimurium/drug effects ; Thiazoles/isolation & purification ; Thiazoles/toxicity
Chemical Substances	Aminoquinolines ; Mutagens ; Thiazoles ; PD 128483 (115688-97-6) ; 4,5-dihydrothiazolo(4,5-f)quinolin-2-amine (115689-52-6) ; thiazolo(4,5-f)quinolin-2-amine (141890-75-7)
Language	English
Publishing date	1992-04
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	206607-5
ISSN	1873-135X ; 0027-5107 ; 1383-5718 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
ISSN (online)	1873-135X
ISSN	0027-5107 ; 1383-5718 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
DOI	10.1016/0165-7992(92)90014-9
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Article: Dopamine autoreceptor agonists as potential antipsychotics. 3.6-Propyl-4,5,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin-2-amine.

Caprathe, B W / Jaen, J C / Wise, L D / Heffner, T G / Pugsley, T A / Meltzer, L T / Parvez, M

Journal of medicinal chemistry

1991 Volume 34, Issue 9, Page(s) 2736–2746

Abstract: A series of rigid tricyclic analogues of the dopamine (DA) agonist PD 118440 [4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine] was synthesized and evaluated for dopaminergic activity and DA autoreceptor selectivity. (R)-(+)-6-Propyl-4,5,5a,6,7, ...

Abstract	A series of rigid tricyclic analogues of the dopamine (DA) agonist PD 118440 [4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine] was synthesized and evaluated for dopaminergic activity and DA autoreceptor selectivity. (R)-(+)-6-Propyl-4,5,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin+ ++-2-amine [+)-6) was identified as the most selective DA autoreceptor agonist from this group of compounds. It inhibited spontaneous locomotor activity (LMA) in rodents, reversed the gamma-butyrolactone (GBL) induced accumulation of rat striatal DOPA and inhibited brain DA neuronal firing, all suggestive of direct DA autoreceptor agonist activity. However, (+)-6 is not completely free of postsynaptic DA activity, as evidenced by its stimulation of LMA in rats at high doses and its ability to produce stereotypy. On the other hand, (-)-6 appears to be a weak partial DA agonist with some effects on brain DA synthesis only at high doses. Like other DA autoreceptor agonists and DA antagonists, (+)-6 inhibited Sidman conditioned avoidance in squirrel monkeys, a test predictive of clinical antipsychotic activity. However, unlike classical antipsychotics, (+)-6 did not induce dystonias in haloperidol-sensitized squirrel monkeys, suggesting a minimal propensity toward extrapyramidal side effects (EPS).
MeSH term(s)	Animals ; Antipsychotic Agents/chemistry ; Dopamine Agents/chemistry ; Dopamine Agents/pharmacology ; Male ; Molecular Structure ; Rats ; Stereoisomerism
Chemical Substances	Antipsychotic Agents ; Dopamine Agents
Language	English
Publishing date	1991-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm00113a010
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Article: 2-amino-4H-3,1-benzoxazin-4-ones as inhibitors of C1r serine protease.

Hays, S J / Caprathe, B W / Gilmore, J L / Amin, N / Emmerling, M R / Michael, W / Nadimpalli, R / Nath, R / Raser, K J / Stafford, D / Watson, D / Wang, K / Jaen, J C

Journal of medicinal chemistry

1998 Volume 41, Issue 7, Page(s) 1060–1067

Abstract: A series of 2-amino-4H-3,1-benzoxazin-4-ones have been synthesized and evaluated as inhibitors of the complement enzyme C1r. C1r is a serine protease at the beginning of the complement cascade, and complement activation by beta-amyloid may represent a ... ...

Abstract	A series of 2-amino-4H-3,1-benzoxazin-4-ones have been synthesized and evaluated as inhibitors of the complement enzyme C1r. C1r is a serine protease at the beginning of the complement cascade, and complement activation by beta-amyloid may represent a major contributing pathway to the neuropathology of Alzheimer's disease. Compounds such as 7-chloro-2-[(2-iodophenyl)-amino]benz[d][1,3]oxazin-4-one (32) and 7-methyl-2-[(2-iodophenyl)amino]benz[d][1,3]oxazin-4-one (37) show improved potency compared to the reference compound FUT-175. Many of these active compounds also possess increased selectivity for C1r compared to trypsin and enhanced hydrolytic stability relative to 2-(2-iodophenyl)-4H-3,1-benzoxazin-4-one (1).
MeSH term(s)	Complement C1r/antagonists & inhibitors ; Oxazines/chemical synthesis ; Oxazines/pharmacology ; Serine Proteinase Inhibitors/chemical synthesis ; Serine Proteinase Inhibitors/pharmacology ; Structure-Activity Relationship ; Trypsin Inhibitors/chemical synthesis ; Trypsin Inhibitors/chemistry ; Trypsin Inhibitors/pharmacology
Chemical Substances	Oxazines ; Serine Proteinase Inhibitors ; Trypsin Inhibitors ; Complement C1r (EC 3.4.21.41)
Language	English
Publishing date	1998-03-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm970394d
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Article: CI-1017, a functionally M1-selective muscarinic agonist: design, synthesis, and preclinical pharmacology.

Tecle, H / Schwarz, R D / Barrett, S D / Callahan, M J / Caprathe, B W / Davis, R E / Doyle, P / Emmerling, M / Lauffer, D J / Mirzadegan, T / Moreland, D W / Lipiniski, W / Nelson, C / Raby, C / Spencer, C / Spiegel, K / Thomas, A J / Jaen, J C

Pharmaceutica acta Helvetiae

2000 Volume 74, Issue 2-3, Page(s) 141–148

Abstract: The five muscarinic receptor subtypes (M1-M5) are characterized by seven helices that define a transmembrane cavity which serves as the binding pocket for agonists and antagonists. The five cavities appear to be topographically different enough to permit ...

Abstract	The five muscarinic receptor subtypes (M1-M5) are characterized by seven helices that define a transmembrane cavity which serves as the binding pocket for agonists and antagonists. The five cavities appear to be topographically different enough to permit subtype selectivity among antagonists but not among classical agonists which tend to be smaller in size than antagonists. It was reasoned that synthesis of muscarinic agonists longer/larger than their classical counterparts might result in subtype selectivity. M1 subtype selectivity was found in a class of 1-azabicyclo[2.2.1]heptan-3-one, O-(3-aryl-2-propynyl) oximes. One of these, CI-1017, improved spatial memory of hippocampally deficient mice and nbM-lesioned rats at doses of 1.0-3.2 and 0.1-0.3 mg/kg, respectively, while producing parasympathetic side effects only at very high doses (100-178 mg/kg). Additionally, CI-1017 inhibited production of amyloidogenic A beta and increased secretion of soluble APP. Thus, CI-1017, besides treating AD symptomatically, may also retard its progression. CI-1017 has recently completed phase I clinical trials.
MeSH term(s)	Animals ; Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Cloning, Molecular ; Humans ; Male ; Maze Learning/drug effects ; Memory/drug effects ; Mice ; Mice, Inbred C57BL ; Muscarinic Agonists/chemical synthesis ; Muscarinic Agonists/pharmacology ; Oximes/chemical synthesis ; Oximes/pharmacology ; Rats ; Receptor, Muscarinic M1 ; Receptors, Muscarinic/drug effects ; Receptors, Muscarinic/metabolism ; Second Messenger Systems/drug effects
Chemical Substances	Bridged Bicyclo Compounds, Heterocyclic ; Muscarinic Agonists ; Oximes ; Receptor, Muscarinic M1 ; Receptors, Muscarinic ; PD 142505-0028 (161774-09-0)
Language	English
Publishing date	2000-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	210383-7
ISSN	0031-6865
ISSN	0031-6865
DOI	10.1016/s0031-6865(99)00027-8
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Article: Kynurenic acid derivatives inhibit the binding of nerve growth factor (NGF) to the low-affinity p75 NGF receptor.

Jaen, J C / Laborde, E / Bucsh, R A / Caprathe, B W / Sorenson, R J / Fergus, J / Spiegel, K / Marks, J / Dickerson, M R / Davis, R E

Journal of medicinal chemistry

1995 Volume 38, Issue 22, Page(s) 4439–4445

Abstract: The ability of a series of substituted kynurenic acids, thienopyridinonecarboxylic acids, and related compounds to inhibit the binding of nerve growth factor (NGF) to the p75 NGF receptor (NGFR) was evaluated in a radioligand binding assay that utilized ... ...

Abstract	The ability of a series of substituted kynurenic acids, thienopyridinonecarboxylic acids, and related compounds to inhibit the binding of nerve growth factor (NGF) to the p75 NGF receptor (NGFR) was evaluated in a radioligand binding assay that utilized a biotinylated derivative of the extracellular domain of p75 NGFR (p75ext) fixed to streptavidin-coated plastic wells. Two compounds, 6-aminokynurenic acid (5h) and the 3-methyl ester of 4,7-dihydro-2-methyl-7-oxothieno[3,2-b]pyridine-3,5-dicarboxylic acid (16), were found to inhibit the binding of [125I]NGF to p75ext with IC50 values in the low micromolar range. Other amino-substituted kynurenic acids also possessed activity at slightly higher concentrations. Several structural features seem to be essential, including the carboxylic acid, a polar group on the benzene ring (or thiophene ring, in the case of analogues of 16), and the C-4 carbonyl group in the pyridinone ring. These compounds were also found to inhibit the binding of [125I]NGF to its receptors in membranes from PC12 cells (which express p75 as well as trka receptors for NGF) and DG44-CHO cells (transfected with full length p75 NGFR). The available data for 5h and 16 do not allow the determination of whether the effects of these compounds are mediated by their interaction with NGF or the NGF receptors.
MeSH term(s)	Animals ; CHO Cells ; Cricetinae ; Guinea Pigs ; Humans ; Kynurenic Acid/analogs & derivatives ; Kynurenic Acid/pharmacology ; Membrane Glycoproteins/antagonists & inhibitors ; Membrane Glycoproteins/chemistry ; Membrane Glycoproteins/metabolism ; Molecular Structure ; Nerve Growth Factors/antagonists & inhibitors ; Nerve Growth Factors/metabolism ; PC12 Cells ; Pyridones/chemical synthesis ; Pyridones/pharmacology ; Quinazolines/chemistry ; Rats ; Receptor, Nerve Growth Factor ; Receptors, Nerve Growth Factor/antagonists & inhibitors ; Receptors, Nerve Growth Factor/chemistry ; Receptors, Nerve Growth Factor/metabolism ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism
Chemical Substances	Membrane Glycoproteins ; Nerve Growth Factors ; PD 90780 ; Pyridones ; Quinazolines ; Receptor, Nerve Growth Factor ; Receptors, Nerve Growth Factor ; Recombinant Proteins ; Kynurenic Acid (H030S2S85J)
Language	English
Publishing date	1995-10-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm00022a008
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Article: The discovery and structure-activity relationships of 1,2,3,6-tetrahydro-4-phenyl-1-[(arylcyclohexenyl)alkyl]pyridines. Dopamine autoreceptor agonists and potential antipsychotic agents.

Wright, J L / Caprathe, B W / Downing, D M / Glase, S A / Heffner, T G / Jaen, J C / Johnson, S J / Kesten, S R / MacKenzie, R G / Meltzer, L T

Journal of medicinal chemistry

1994 Volume 37, Issue 21, Page(s) 3523–3533

Abstract: A novel dopamine (DA) autoreceptor agonist, 1,2,3,6-tetrahydro-4-phenyl-1- [(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine (14), was identified. The structure-activity relationships surrounding this compound were studied by synthesis of analogues and ... ...

Abstract	A novel dopamine (DA) autoreceptor agonist, 1,2,3,6-tetrahydro-4-phenyl-1- [(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine (14), was identified. The structure-activity relationships surrounding this compound were studied by synthesis of analogues and evaluation of their dopaminergic activity. The cyclohexene substitution pattern was varied along with the length of the chain connecting the 1,2,3,6-tetrahydro-4-phenylpyridine to the cyclohexene. Compound 14, having the 1,3-substitution pattern and a single methylene chain, was the most potent. The 1,2,3,6-tetrahydro-4-phenylpyridine could be replaced by other aryl-cyclic amines with a slight loss in activity. The phenyl group on the cyclohexene ring could be para substituted; electron-donating groups were better tolerated than electron-withdrawing groups. Finally, the enantiomers of 14 were resolved via the 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate salts. Although both isomers were partial DA agonists, the (+)-enantiomer had higher intrinsic activity than the (-)-enantiomer. Syntheses were developed that allowed rapid preparation of analogues. An X-ray crystal structure determination of an intermediate identified the (+)-isomer of 14 as having R configuration. This compound, designated CI-1007 (PD 143188), was found to have antipsychotic-like activity in behavioral tests; in particular, it was orally active in the conditioned avoidance test in squirrel monkeys with an ED50 of 0.6 mg/kg. The overall profile suggests that (R)-(+)-14 may be a clinically useful antipsychotic agent.
MeSH term(s)	1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/analogs & derivatives ; Action Potentials/drug effects ; Animals ; Antipsychotic Agents/chemistry ; Antipsychotic Agents/pharmacology ; Avoidance Learning/drug effects ; Brain/metabolism ; CHO Cells ; Cricetinae ; Crystallography, X-Ray ; Cyclic AMP/metabolism ; Cyclohexanes/chemistry ; Cyclohexenes ; Dopamine/biosynthesis ; Dopamine Agonists/chemistry ; Dopamine Agonists/pharmacology ; Mice ; Models, Molecular ; Molecular Structure ; Motor Activity ; Pyridines/chemistry ; Pyridines/metabolism ; Pyridines/pharmacology ; Rats ; Receptors, Dopamine/metabolism ; Saimiri ; Stereoisomerism ; Structure-Activity Relationship ; Substantia Nigra/physiology
Chemical Substances	Antipsychotic Agents ; Cyclohexanes ; Cyclohexenes ; Dopamine Agonists ; Pyridines ; Receptors, Dopamine ; cyclohexene (12L0P8F7GN) ; 1,2,3,6-tetrahydro-4-phenyl-1-((3-phenyl-3-cyclohexen-1-yl)methyl)pyridine (150013-70-0) ; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (9P21XSP91P) ; Cyclic AMP (E0399OZS9N) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	1994-10-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm00047a010
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Article: Pharmacological profile of the dopamine partial agonist, (+/-)-PD 128483 and its enantiomers.

Meltzer, L T / Caprathe, B W / Christoffersen, C L / Corbin, A E / Jaen, J C / Ninteman, F W / Pugsley, T A / Serpa, K A / Shih, Y H / Whetzel, S Z

The Journal of pharmacology and experimental therapeutics

1993 Volume 266, Issue 3, Page(s) 1177–1189

Abstract: PD 128483, ((+/-)-4,5,5a,6,7,8-hexahydro-6-methylthiazolo[4,5-f]-quinolin+ ++-2-amine, maleate (1:1)), is a racemic compound that is a p.o. active dopamine (DA) partial agonist that has DA autoreceptor agonist effects and displays antipsychoticlike ...

Abstract	(+/-)-PD 128483, ((+/-)-4,5,5a,6,7,8-hexahydro-6-methylthiazolo[4,5-f]-quinolin+ ++-2-amine, maleate (1:1)), is a racemic compound that is a p.o. active dopamine (DA) partial agonist that has DA autoreceptor agonist effects and displays antipsychoticlike activity in preclinical tests. In in vitro receptor binding assays, (+/-)-PD 128483 and its enantiomers bound selectively to DA D-2 receptors vs. DA D-1 receptors and showed no affinity for adrenergic alpha-1 or serotonin1A receptors, but had affinity for adrenergic alpha-2 receptors. In tests of DA agonist effects, including reversal of the tau-butyrolactone-stimulated increase in brain dopa synthesis in striatum and inhibition of DA neuronal firing, the rank order of efficacy was (+)-PD 128483 > (+/-)-PD 128483 > (-)-PD 128483. (+/-)-PD 128483 and (+)-PD 128483 inhibited, whereas (-)-PD 128483 increased, brain DA synthesis in normal rats. (+/-)-PD 128483 and (-)-PD 128483 inhibited spontaneous locomotion in rats and did not produce locomotor stimulation or stereotypies. In contrast, (+)-PD 128483 inhibited locomotor activity at low doses, but at relatively high doses increased locomotion and induced stereotypy in rats. (-)-PD 128483 consistently inhibited Sidman avoidance responding in squirrel monkeys. (+/-)-PD 128483 inhibited Sidman avoidance responding in one group of monkeys, but had minimal effects in another group. (+)-PD 128483 did not inhibit avoidance responding. In squirrel or cebus monkeys sensitized to the acute dystonic effects of haloperidol, only (-)-PD 128483 induced extrapyramidal dysfunction. These results indicate that (+/-)-PD 128483 is a DA partial agonist which produces DA autoreceptor agonist effects and has a preclinical behavioral profile suggestive of antipsychotic activity.
MeSH term(s)	4-Butyrolactone/pharmacology ; Aminoquinolines/metabolism ; Aminoquinolines/pharmacology ; Amphetamine/pharmacology ; Animals ; Apomorphine/pharmacology ; Avoidance Learning/drug effects ; Behavior, Animal/drug effects ; Cebus ; Dopamine/biosynthesis ; Dopamine/metabolism ; Dopamine Agents/pharmacology ; Dose-Response Relationship, Drug ; Extrapyramidal Tracts/drug effects ; Extrapyramidal Tracts/physiology ; Male ; Mice ; Motor Activity/drug effects ; Neurons/drug effects ; Neurons/physiology ; Norepinephrine/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Dopamine/metabolism ; Saimiri ; Serotonin/biosynthesis ; Serotonin/metabolism ; Stereoisomerism ; Stereotyped Behavior/drug effects ; Stimulation, Chemical ; Thiazoles/metabolism ; Thiazoles/pharmacology
Chemical Substances	Aminoquinolines ; Dopamine Agents ; Receptors, Dopamine ; Thiazoles ; PD 128483 (115688-97-6) ; Serotonin (333DO1RDJY) ; Amphetamine (CK833KGX7E) ; Apomorphine (N21FAR7B4S) ; 4-Butyrolactone (OL659KIY4X) ; Dopamine (VTD58H1Z2X) ; Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	1993-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
Database	MEDical Literature Analysis and Retrieval System OnLINE

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