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PubMed1983

2-Benzazepines. 2. Thiazolo[5,4-d][2]benzazepines.

As part of a program in the area of annelated 2-benzazepines, several thiazolo[5,4-d))[2]benzazepines were prepared. Treatment of the bromo ketones 7-9 with various thio amides gave the thiazoles 10-15, which when treated with methylamine gave the title compounds. The preliminary pharmacology of these compounds showed that they had central nervous system activity similar to the 1,4-benzodiazepines, such as diazepam. The thiazolo[5,4-d][2]benzazepines were also found to bind to the benzodiazepine-receptor complex, indicating that their pharmacological actions are probably related to the 1,4-benzodiazepines.

Animals↗
PubMed1983

2-benzazepines. 5. Synthesis of pyrimido[5,4-d][2]benzazepines and their evaluation as anxiolytic agents.

A series of 5H-pyrimido[5,4-d][2]benzazepines has been synthesized, starting from the corresponding 2-benzazepin-5-ones, and evaluated as potential anxiolytic agents. Selected compounds from this series show a pharmacological profile of action different than that of diazepam. They are more potent than diazepam in the anti-pentylenetetrazole test and in the [3H]diazepam binding assay, yet show less activity in the inclined screen test. A pharmacological data profile is given for 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2]benzazepine (7c). The structure-activity relationships of these potential anxiolytic agents are discussed.

Animals↗
PubMed1983

2-benzazepines. 6. Synthesis and pharmacological properties of the metabolites of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2]benzazepine.

The 2-benzazepine 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2]benzazepine (1) has been selected for development as an anxiolytic agent. In support of this program, we have confirmed by chemical synthesis the structures of three in vitro (rat liver homogenate) metabolites of 1 and confirmed the structure of the major in vivo (dog and man) metabolite of 1, compound 2. Two of the metabolites, arising from hydroxylation of the pyrimidobenzazepine ring at the 5-position (2) and N-oxide formation at the 3-position of the pyrimidobenzazepine ring (3), were found to be as active as 1 in a series of pharmacological tests. The third metabolite, formed by hydroxylation of the 7-phenyl group in the 4-position (4), was found to be inactive in the same pharmacological screens.

Animals↗
PubMed1983

2-Benzazepines. 4. [1,2,3]Triazolo[4,5-d][2]benzazepines and dibenzo[c,f][1,2,3]triazolo[3,4-a]azepines: synthesis and evaluation as central nervous system agents.

The facile synthesis of [1,2,3]triazolo((4,5-d][2]benzazepines and dibenzo[c,f][1,2,3]triazolo[3,4-a]azepines by the addition of sodium azide to acetylenic benzophenones is described. Examination of the pharmacological data indicates that selected triazolobenzazepines are as potent as diazepam in the anti-pentylenetetrazole test and are weaker in the inclined screen and rotarod tests, suggesting that these compounds have antianxiety properties similar to diazepam with fewer deficits in motor coordination. In addition, a possible diazepam antagonist was found in the triazolo-benzazepine series. The dibenzotriazoloazepines were found to be inactive in four standard CNS screening procedures.

Animals↗
PubMed1996

Fluorinated benzazepines: 1. Synthesis, radiosynthesis and biological evaluation of a series of substituted benzazepines as potential radiotracers for positron emission tomographic studies of dopamine D-1 receptors.

We have prepared N-alkyl, aryl, fluoroalkyl, fluoroaryl and iodoaryl derivatives of 7-chloro-8-hydroxy-3-methyl-1-(3'-aminophenyl)-2,3,4,5-tetrahydro-1 H-3-benzazepine (SCH 38548) as high-affinity ligands for the dopamine D1 receptor. Binding affinities of the compounds for dopamine D1, D2, and serotonin 5-HT2 receptor sites in rat brain homogenates were measured. The affinity of SCH 38548 for dopamine D1 receptors was found to be 0.53 +/- 0.46 nM, whereas lower affinities (in the micromolar range) for dopamine D2 and serotonin 5-HT2 receptors were found. Alkylation (ethyl, n-propyl and benzyl) and acylation (benzoyl) of the amino group of SCH 38548 did not decrease affinities for the D1 receptors significantly. The fluoroethyl, fluoropropyl, and fluorobenzyl derivatives showed approximately an 8-fold, 9-fold, and 3-fold decrease in affinity for the D1 sites compared to SCH 38548. The N-4-fluorobenzoyl derivative, however, showed a similar affinity for the D1 sites as for SCH 38548. All four fluorinated derivatives exhibited weak binding at D2 and serotonin 5-HT2 receptors. The N-(4-18F-fluorobenzoyl)SCH 38548 was prepared by reacting SCH 38548 with 4-18F-fluorobenzoyl fluoride in 2-5% radiochemical yield with a specific radioactivity of approximately 600-700 Ci/mmol. The N-(3-18F-fluoropropyl)SCH 38548 was prepared by reacting SCH 38548 with 18F-fluoropropyl iodide in 2-5% radiochemical yield with a specific radioactivity of approximately 600-700 Ci/mmol. N-(4-18F-fluorobenzoyl)SCH 38548 failed to localize in the dopaminergic sites in the rat and rhesus monkey brain. Biodistribution of N-(3-18F-fluoropropyl)SCH 38548 in rats showed specific uptake and retention (0.64% injected dose/g at 30 min) of the radiotracer in the striata, with striata-to-cerebellum ratios reaching 12 at 2 h postinjection (p.i.). Positron emission tomography scans in rheusus monkeys indicate selective uptake of the radiotracer in the striata. After IV injection of N-(3-18F-fluoropropyl)SCH 38548, a rapid brain uptake of the tracer from blood was observed. Initial uptake in the striata and cerebellum was approximately 0.02% of injected dose/cc. Nonspecific uptake from the tissue surrounding the striata cleared slowly. The striata-to-cerebellum ratio increased from 1.20 to 3.5 min postinjection to approximately 2.5 at 120 min p.i. The specific uptake of N-(3-18F-fluoropropyl)SCH 38548 in the striata was displaced by IV administration of SCH 24518 (2 mg/kg).

Animals↗
PubMed1986

Dopamine receptor agonists: 3-allyl-6-chloro-2,3,4,5-tetrahydro- 1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-diol and a series of related 3-benzazepines.

The N-allyl derivative (SK&F 85174) of 6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-dio l (SK&F 82526) not only retains the exceptional D-1 agonist potency of its parent but also displays reasonably potent D-2 agonist activity, as measured by a dopamine-sensitive adenylate cyclase test and a rabbit ear artery assay, respectively. Several additional N-substituted compounds were prepared to explore the D-2/D-1 agonist relationship. The N-methyl analogue retained good D-2 agonist potency, but this substitution converted D-1 agonist activity into antagonist activity. Most other N-substituents sharply decreased D-2 agonist potency including the N-n-propyl group. This observation was surprising since the introduction of mono- or di-N-n-propyl substituent(s) is commonly linked with retention or enhancement of D-2 agonist potency in other series of dopamine agonists. The N-(2-hydroxyethyl) analogue retains about one-fourth the D-2 potency of SK&F 85174. Several synthetic methods were used to prepare these compounds. N-Allylation of a trimethoxybenzazepine followed by cleavage of the methyl ethers with boron tribromide was the preferred method. Other methods used were direct alkylation of the trihydroxy secondary amine, i.e., SK&F 82526, and an acylation-amide reduction-cleavage method.

Alkylation↗
PubMed2005

Complete 1H and 13C NMR spectral assignment of N-aralkylsulfonamides, N-sulfonyl-1,2,3,4-tetrahydroisoquinolines and N-sulfonyl-2,3,4,5-tetrahydro-1H-2-benzazepines. Conformational analysis of N-[((3',4'-dichlorophenyl)methyl)sulfonyl]-3-methyl-2,3,4,5-tetrahydro-1H-2-benzazepin.

The complete and unambiguous assignment of the 1H NMR and 13C NMR spectra of 26 N-aralkylsulfonamides, N-sulfonyl-1,2,3,4-tetrahydroisoquinolines and N-sulfonylbenz[c]azepines was performed on the basis of APT, DEPT, homonuclear (gs-COSY) and 1H-detected heteronuclear one-bond (gs-HMQC) and long-range (gs-HMBC) correlation experiments. The methylated 2,3,4,5-tetrahydro-1H-2-benzazepine derivative 26 adopts a chair conformation as determined by 1H-1H coupling analysis and gamma-gauche effects. This is supported by a single-crystal X-ray structure analysis.

Journal Article↗
PubMed1996

(+/-)-3-[4'-(N,N-dimethylamino)cinnamyl]benzazepine analogs: novel dopamine D1 receptor antagonists.

Neurochemical studies and structure-activity relationships of dopamine D1 receptor ligands suggest that their intrinsic activity may depend on the conformational state or binding site at which they interact on the receptor protein. Important differences in the modes of binding of these ligands may confer their agonist, partial agonist, or antagonist properties. In an effort to develop novel dopamine D1 antagonists and investigate the D1 antagonist pharmacophore, a series of (+/-)-(N-alkylamino)benzazepines were prepared in which (+/-)-7-chloro-8-hydroxy-3-[6-(N,N-dimethylamino)hexyl]-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine (1) demonstrated the highest binding affinity (Ki = 49.3 nM) and selectivity to dopamine D1 receptors. This compound inhibited dopamine-stimulated adenylyl cyclase, in rat caudate, confirming a D1 receptor antagonist profile. From this initial series of N-alkylamino-substituted benzazepines, structure-activity relationships suggested that the terminal amino function was necessary for optimal binding affinity and selectivity at D1 vs D2 sites. Further, addition of this side chain to the D1 agonist pharmacophore (e.g., 7,8-dihydroxy-3-[4-(N,N-dimethylamino)butyl]-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine) greatly decreased binding affinity at D1 receptors. These data suggested that a binding domain that may be unique to the D1 antagonists may have been identified. In an attempt to exploit an apparent amine-accepting binding domain on the D1 receptor, a series of (+/-)-3-[4'-(N,N-dimethylamino)cinnamyl]benzazepine analogs was designed and prepared, as D1 antagonists. In this series, (+/-)-7-chloro-8-hydroxy-3-[4'-(N,N-dimethylamino)cinnamyl]-1-phenyl-2,3,4,5 -tetrahydro-1H-3-benzazepine (6a) showed the highest binding affinity (Ki = 60.3 nM) for dopamine D1 receptors. Compound 6a was a potent dopamine D1 antagonist as evidenced by its ability to block dopamine-stimulated adenylyl cyclase activity in rat caudate (predicted Ki value = 18.4 nM). Molecular modeling studies demonstrated that the most potent and selective dopamine D1 antagonists, in both series, contained terminal amino groups 8-9 A away from the 3-position benzazepine nitrogen. Compounds that lacked a terminal amine function or where this moiety was less than 7 A away from the benzazepine nitrogen demonstrated significantly lower binding affinities. Therefore, this series of (+/-)-3-[4'-(N,N-dimethylamino)cinnamyl]benzazepines also appears to be identifying an amine-accepting binding domain on the dopamine D1 receptor protein that may be further explored for the development of novel dopamine D1 antagonists.

Adenylyl Cyclases↗
PubMed1995

Stimulation of adenylate cyclase activity by benzazepine D-1 dopamine agonists with varying efficacies in the 6-hydroxydopamine lesioned rat--relationship to circling behaviour.

The ability of benzazepine D-1 dopamine agonists with varying efficacies in stimulating adenylate cyclase and to induce contralateral circling was investigated in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. In the 6-hydroxydopamine lesioned rats, the benzazepines SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), SKF 75670 (3-CH3 analogue), SKF 80723 (6-Br analogue), SKF 83959 (6-Cl, 3-CH3, 3'-CH3 analogue), SKF 83565 (6-Cl, 3-CH3, 3'-Cl analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue), all produced contralateral circling. The rank order of efficacies (maximal effect, Emax) being, SKF 83565 = SKF 75670 = SKF 83959 = SKF 80723 > SKF 38393 >> SKF 82958. In striatal slices from the intact hemisphere, dopamine, SKF 82958, SKF 80723 and SKF 75670 stimulated adenylate cyclase activity. The rank order of efficacies being SKF 82958 (109%) = dopamine (100%) = SKF 80723 (98%) > SKF 75670 (72%). Although, SKF 38393 (67%), SKF 83565 (64%) and SKF 83959 (59%) tended to stimulate adenylate cyclase activity, this effect did not reach statistical significance. In the 6-hydroxydopamine lesioned hemisphere, basal levels of adenylate cyclase activity were lower (-25%) than in the intact hemisphere. The maximal stimulation of adenylate cyclase activity (expressed as % basal levels) produced by dopamine and the benzazepines in the denervated striatum was greater than observed in the intact striatum. The rank order of efficacies in the dopamine denervated striatum being SKF 82958 (124%) > SKF 80723 (109%) = dopamine (100%) > SKF 38393 (82%) = SKF 83959 (77%) = SKF 83565 (70%) > SKF 75670 (55%). Moreover, dopamine stimulated adenylate cyclase activity in the denervated striatum with greater potency than in the intact side. The ability of the benzazepine derivatives to induce circling in the 6-hydroxydopamine lesioned rat is consistent with the general increase in the efficacies of dopamine and benzazepine stimulated adenylate cyclase activity in the dopamine denervated striatum. However, the maximal effects for inducing circling and stimulating adenylate cyclase activity do not correspond (e.g. SKF 82958 and SKF 75670). This discrepancy may reflect the involvement of other factors including a behavioural role for extrastriatal D-1 dopamine receptors and/or transduction systems other than adenylate cyclase.

Adenylyl Cyclases↗
PubMed2000

Chemistry and biological activity of new 3-benzazepines.

This review summarizes our experiments investigating structure-activity relationships of 3-benzazepines. Three 7, 8-dihydroxy-3-benzazepines [7-9] were cytotoxic to human promyelotic leukaemia HL-60 cells. Compound [9] showed the highest cytotoxicity and the activity was twice as high as that of dopamine (DA, [11]). Three active compounds [7-9] produced radicals, whereas other less potent benzazepines [1-6, 10] did not produce radicals. Furthermore, cytotoxic 3-benzazepines [7-9] also enhanced the decay of ascorbic acid in rat brain homogenate. Two 7,8-dimethoxy-3-benzazepines [5, 10] were able to form a complex with the replicative form of plasmid DNA. The multidrug resistance (MDR) P-glycoprotein (Pgp) efflux pump of mouse lymphoma cells was inhibited by three compounds [5, 8, 10]. Compound [8] has the highest activity in MDR reversal and is two times more potent than verapamil. Three cytotoxic 3-benzazepines [7-9] showed inhibitory effects against reverse transcriptase (RT) of Moloney leukemia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Activation of the 5-HT1C receptor expressed in Xenopus oocytes by the benzazepines SCH 23390 and SKF 38393.

1. A cloned 5-HT1C receptor expressed in Xenopus laevis oocytes was used to characterize the action of four dopamine D1-selective benzazepines at the 5-HT1C receptor. Additionally, the apparent binding of the D1-selective benzazepines to 5-HT1C receptors was measured in the choroid plexus of the pig. 2. In voltage-clamped oocytes expressing the cloned 5-HT1C receptor, 5-hydroxytryptamine (5-HT) elicited a characteristic inward current response with an EC50 of 13 nM. SCH 23390 acted as a stereoselective agonist (or partial agonist) with an EC50 of about 550 nM. SKF 38393 (1 microM-1 mM), SKF 77434 (100 microM), and SKF 82958 (100 microM) also acted as agonists (or partial agonists) at the cloned 5-HT1C receptor. SKF 38393 was not stereoselective at the 5-HT1C receptor. 3. The response to SCH 23390 activated slowly and, although the response contained many oscillations characteristic of the activation of the phosphatidylinositol signal transduction system, SCH 23390 rarely elicited the rapid spike-like response seen routinely in response to 5-HT. However, the responses to SKF 38393, SKF 77434, and SKF 82958 were identical in appearance to the response to 5-HT, except that the responses to the benzazepines were smaller. These comparisons were made by applying both a benzazepine and 5-HT to each individual oocyte expressing the cloned 5-HT1C receptor. 4. Consistent with the responses measured in oocytes, SCH 23390 bound stereoselectively to 5-HT1C receptors in the choroid plexus of the pig (Ki = 6.3 nM), and SKF 38393 bound non-stereoselectively with lower affinity (Ki = 2.0-2.2 microM).5. It is concluded that while these benzazepines demonstrate selectivity for the dopamine D1 receptor, they also can act as agonists or partial agonists at the 5-HT1c receptor in situ and as expressed in Xenopus oocytes. The oocyte expression system is useful for studies of the functional pharmacology of these 5-HTic receptors. Information about the pharmacological actions and variations in stereoselectivity among dopamine and 5-HT receptors should be of interest in modelling the interactions of ligands with these G-protein coupled receptors, and in the testing of such models through receptor mutagenesis.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Agonist and antagonist properties of benzazepine and thienopyridine derivatives at the D1 dopamine receptor.

Nine structurally related 1-phenyl-1H-3-benzazepine derivatives and two thienopyridines were tested for agonist and antagonist properties at the adenylate cyclase-coupled D1 dopamine receptor in homogenates of the striatum of the rat. The benzazepines SK&F 77434 and SK&F 82958, both of which contain a catechol ring, were agonists; the intrinsic activity of SK&F 77434 was similar to that of SK&F 38393, whereas SK&F 82958 was a full agonist. The remaining benzazepines inhibited the stimulation of adenylate cyclase by dopamine. Antagonist potency depended on the nature of the substituent at position 7 of the benzazepine molecule, 7-halogen compounds being the most potent. The Ki values, obtained from analysis of the antagonism of dopamine-stimulated adenylate cyclase, were significantly correlated with the Ki values for displacement of D1 ligands in binding experiments. Furthermore, antagonist activity of the resolved racemic benzazepine SK&F 83566 resided almost exclusively in the R-enantiomer. The thienopyridine derivatives SK&F 89641 and SK&F 89145 were partial agonists with greater efficacies than SK&F 38393.

Adenylyl Cyclase Inhibitors↗
PubMed1983

Determination of a pyrimido-benzazepine anxiolytic agent and its 5-hydroxy metabolite in whole blood, plasma and urine by gas--liquid chromatography with electron-capture detection and by high-performance liquid chromatography.

Electron-capture gas--liquid chromatographic and reversed-phase high-performance liquid chromatographic assays are described for the quantitation of the compound, 9-chloro-7-(2-chlorophenyl)-5H-pyrimido [5,4-d] [2]-benzazepine, [I], a member of the benzazepine class of compounds undergoing clinical evaluation as anxiolytic agents. Studies on the biotransformation of [I] in the rat and dog showed that the compound was metabolized mainly by hydroxylation to yield the 5-hydroxy compound, [II], 9-chloro-7-(2-chlorophenyl)-5H-pyrimido [5,4-d] [2]-benzazepin-5-ol (major metabolite), along with the formation of lesser amounts of the N-oxide, [III], 9-chloro-7-(2-chlorophenyl)-5H-pyrimido [5,4-d] [2]-benzazepine 3-oxide, and the phenolic analogue, [IV], 3-chloro-4-(9-chloro-5H pyrimido-[5,4-d] [2] benzazepin-7-yl)phenol. This report describes the quantitation of [I] and [II] (major metabolite) in plasma using the above analytical techniques, both in preclinical studies in the dog and in clinical pharmacokinetic studies in man.

Animals↗
PubMed1992

Competitive antagonism of glutamate receptor channels by substituted benzazepines in cultured cortical neurons.

Whole-cell recordings from rat cortical neurons in dissociated cell culture were used to study the antagonism of glutamate receptors by several lipophilic benzazepine analogues of 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (DDHB). DDHB and three substituted derivatives, 4-bromo-, 7-methyl-, and 8-methyl-DDHB, inhibited the activation of N-methyl-D-aspartate (NMDA) receptors at both the NMDA recognition site and the glycine allosteric site. In addition, all four compounds blocked the activation of non-NMDA receptors by kainate and L-glutamate. Antagonism by the four benzazepines was equivalent at holding potentials from -80 mV to +50 mV. Both the onset of and recovery from block of the agonist-gated currents were complete within seconds. Antagonist affinity was calculated from the displacement of steady state concentration-response curves for kainate, L-glutamate, glycine, and NMDA, based on the Gaddum-Schild relationship (dose ratio = 1 + [antagonist]/KB). The most potent blocker, 8-Me-DDHB, had an apparent dissociation constant (KB) of 470 nM at the glycine allosteric site and 27 microM at the NMDA recognition site. The apparent dissociation constant of 8-Me-DDHB for non-NMDA receptors was 6.4 microM when kainate was the agonist and 9.6 microM when L-glutamate was the agonist. Unsubstituted DDHB showed slightly higher affinity for the NMDA recognition site (KB = 16 microM) but was less potent than 8-Me-DDHB at the glycine allosteric site and at non-NMDA receptors (KB = 3 and 65 microM, respectively). At all three sites, the inhibitory actions of these benzazepine derivatives were consistent with a simple competitive mechanism of antagonism. In addition, the antagonist potency of the parent compound, DDHB, against kainate, NMDA, and glycine was equal to or greater than that of other bicyclic antagonists, including kynurenic acid, indole-2-carboxylic acid, and quinoxaline-2,3-dione. Substituted benzazepines represent a new class of glutamate receptor antagonists that show competitive action, significant potency at multiple sites, and a high degree of lipophilicity.

Animals↗
PubMedDate not supplied

Benzazepine metabolism revisited. Evidence for the formation of novel amine conjugates.

Three novel metabolites of the benzazepine SK&F 86466 (6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine) have been isolated from dog urine and characterized by tandem mass spectrometry, using fast atom bombardment and thermospray ionization, and 1H and 13C NMR spectroscopy. The parent drug undergoes oxidation to yield an N-oxide or N-demethylation to yield the primary metabolite SK&F 101055 (6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine). This desmethyl metabolite then undergoes N-sulfoconjugation to yield 6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine-3-N-sulfonate. Two glucuronide conjugates derived from the desmethyl metabolite were also isolated and characterized. One glucuronide is formed from an intermediate carbamic acid, formally derived from the addition of CO2 to the desmethyl benzazepine. A second glucuronide is derived from an intermediate hydroxylamine metabolite. Methodology for characterizing the carbamyl glucuronide was developed, using an ethanolysis reaction to give a stable ethyl carbamate derivative that can then be characterized by GC-MS. This methodology should prove useful in establishing whether such carbamylation reactions occur with other amines.

Adrenergic alpha-Antagonists↗
PubMed1995

The differential behavioural effects of benzazepine D1 dopamine agonists with varying efficacies, co-administered with quinpirole in primate and rodent models of Parkinson's disease.

The effects of co-administration of quinpirole with benzazepine D1 dopamine (DA) agonists possessing full/supramaximal (SKF 80723 and SKF 82958), partial (SKF 38393 and SKF 75670) and no efficacies (SKF 83959) in stimulating adenylate cyclase (AC) were investigated in rodent and primate models of Parkinson's disease (PD). In rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle, co-administration of SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), SKF 75670 (3-CH3 analogue), SKF 80723 (6-Br analogue), SKF 83959 (6-Cl, 3-CH3, 3'-CH3 analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue) strongly potentiated the contralateral circling induced by quinpirole. In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated common marmosets, administration of quinpirole alone increased locomotor activity and reversed motor deficits. Grooming and oral activity were unaltered. Co-administration of SKF 38393 and SKF 75670 inhibited the quinpirole-induced changes in locomotor activity and motor disability. The combined treatment of SKF 80723 or SKF 82958 with quinpirole had no overall effect on locomotor activity or motor disability. In contrast, SKF 83959 extended the duration of the quinpirole-induced increase in locomotor activity with corresponding decreases in motor disability. Co-administration of high doses of SKF 82958 and more especially SKF 83959 and SKF 80723, with quinpirole induced hyperexcitability and seizures. Oral activity and grooming were unaltered following the co-administration of benzazepine derivatives with quinpirole. The ability of some benzazepine D1 DA agonists to prolong the antiparkinsonian effects of quinpirole in the MPTP-treated marmoset may indicate a role for certain D1 DA agonists in the clinical treatment of PD. In general, the behavioural responses to the combined administration of benzazepines with quinpirole in the 6-OHDA lesioned rat and more especially the MPTP-treated marmoset failed to correlate with their ability to stimulate AC. These observations further implicate a behavioural role for D1 DA receptors not linked to AC.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Stereoisomeric probes for the D1 dopamine receptor: synthesis and characterization of R-(+) and S-(-) enantiomers of 3-allyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine and its 6-bromo analogue.

Substituted 1-phenyl-3-benzazepines (e.g., SKF 38393 and fenoldopam) exhibit stereoselectivity in moderately high-affinity binding to and partial agonist activation of D1 dopamine receptors. The 3-allyl (APB) and the 3-allyl-6-chloro (6-Cl-APB) analogues of SKF 38393 are reported to have higher affinity and selectivity for the D1 DA receptor and higher in vivo central neuropharmacologic activity than SKF 38393. We recently reported the corresponding 3-allyl-6-bromo analogue (6-Br-APB) also to be a high-affinity D1 agonist. We now describe the synthesis and characterization of the R-(+) and S-(-) enantiomers of both APB and 6-Br-APB and their comparison with corresponding enantiomers of SKF 38393 with respect to D1 receptor binding affinity and D1 and D2 selectivity. The R-(+) enantiomers of both novel substituted 1-phenyl-3-benzazepines bound to the D1 receptor sites in rat forebrain tissue with much higher affinity and selectivity than their S-(-) antipodes. R-(+)-3-Allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine [(R)-(+)-6-Br-APB, 18] exhibits the highest affinity of the reported 1-phenyl-3-benzazepine D1 agonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗