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At least 19 recordsLinked to original sources

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↗

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↗

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↗

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↗

PubMed1991

Stereospecific microbial reduction of 4,5-dihydro-4-(4-methoxyphenyl)-6-(trifluoromethyl-1H-1)-benzazepin+ ++-2-o ne.

A key intermediate, (3R-cis)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluorome thyl)- 2H-1-benzazepin-2-one (compound II or SQ32191), with high optical purity was made by the stereoselective microbial reduction of the parent ketone 1. Several strains of bacterial and yeast cultures were screened for the ability to catalyse the stereoselective reduction of 4,5-dihydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)-1H-1-benzazepin++ +-2,3-dione [compound I or SQ32425]. Microorganisms from the genera Nocardia, Rhodococcus, Alkaligenes, Corynebacterium, Arthrobacter, Hansenula, and Candida reduced compound I to compound II with 60-70% conversion yield. In contrast, microorganisms from the genera Pseudomonas and Acinetobacter reduced compound I stereospecifically to (trans)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromet hyl-2H- 1-benzazepin-2-one (compound III or SQ32408). Among various cultures evaluated, N. salmonicolor SC6310 effectively catalysed the transformation of compound I to compound II with 96% conversion yield at 1.5-2.0 gl-1 concentration. Compound II was isolated and identified by NMR analysis, mass spectrometry, and comparison to an authentic sample. Preparative scale fermentation process and transformation process were developed using cell suspensions of N. salmonicolor SC6310 to catalyse the transformation of compound I to compound II. The isolated compound II had a melting point of 222 degrees C (reference 221-223 degrees C), optical rotation of +130.4 (reference +128 degrees C), and optical purity of greater than 99.9% as analyzed by NMR and chiral HPLC.

Bacteria↗

PubMed1987

125I-iodinated benzazepines bind to melanin: implications for the noninvasive localization of pigmented melanomas.

Both the 5-R and the 5-S enantiomers of [125I]2,3,4,5-tetrahydro-8-iodo-3-methyl-5-phenyl-1H-3-benzazepin- 7-ol bind to melanin. The interaction between the 5-R enantiomer and melanin permits visualization of melanomas in mice with a noninvasive imaging procedure. Two lines of evidence suggest that the interaction between iodinated ligands and melanin is not related to the D-1 dopamine receptor, a known target for the 5-R enantiomer: first, melanin binds both enantiomers of the 125I-iodinated benzazepine while the D-1 receptor binds only the 5-R enantiomer; second, the melanin binding site displays only a 5-fold difference in affinity towards the R- and S-enantiomers of SCH 23390 while the D-1 receptor displays a 100-fold difference in affinity towards these two molecules. Because both enantiomers of the iodinated benzazepine bind to a human pigmented melanoma, we propose that such compounds may be of use in the diagnosis of pigmented melanoma: in addition, we discuss the possible application of these molecules as a supplement to existing technology for the localization of pigmented melanomas.

Animals↗

PubMed1992

(+/-)-3-allyl-7-halo-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines as selective high affinity D1 dopamine receptor antagonists: synthesis and structure-activity relationship.

Substituted 1-phenyl-3-benzazepines form a class of compounds possessing potent and selective affinity for the D1 DA receptor. 7,8-Dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF 38393) and its 6-halo analogues are potent and selective D1 receptor agonists. Recently, the 3-allyl derivatives of SKF 38393 and its analogues were described as selective D1 agonists with higher D1 efficacy and CNS potency. In order to extend these results to compounds in the 7-halo-8-hydroxy-substituted antagonist series, we have synthesized and pharmacologically characterized 3-allyl analogues of 7-substituted (Cl, Br, H) 8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines. These 3-allyl derivatives were compared with their 3-methyl and 3-unsubstituted analogues in terms of their D1 receptor affinity and selectivity. The results have been used to generate structure-affinity relationships. The D1 receptor affinity, for 3-substitution, is found to be in the order: methyl greater than allyl greater than H. For 7-substitution, the affinity is in the order: Cl = Br greater than H. The 3-allyl compounds show affinity close to that of the parent (3-methyl) compounds while exhibiting a slightly diminished D1 selectivity. However, the greater lipophilicity of the 3-allyl compounds may enable them to cross the blood-brain barrier more readily and thereby exhibit higher in vivo CNS potency. Thus 3-allylbenzazepines have potential as high affinity selective D1 antagonists.

Animals↗

PubMed1989

(+/-)-7-chloro-8-hydroxy-1-(4'-[125I]iodophenyl)-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine: a potential CNS D-1 dopamine receptor imaging agent.

Synthesis, radiolabeling, and in vitro and in vivo properties of an iodinated benzazepine, (+/-)-7-chloro-8-hydroxy-1-(4'-[125I]iodophenyl)-3- methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, [125I]FISCH, as a potential imaging agent for evaluation of central nervous system (CNS) D-1 dopamine receptors in humans, were investigated. After an iv injection, this benzazepine derivative showed good brain uptake in rats (2.27, 1.40, 0.55% dose/whole brain at 2, 15, and 60 min, respectively). The striatum/cerebellum ratio was high (2.47 at 60 min after the injection). The binding affinity of this agent in rat striatum tissue preparation displayed a Kd of 1.43 +/- 0.15 nM. Competition data (in vitro) showed the following rank order of potency: SCH-23390 greater than (+/-)-FISCH greater than (+/-)-IBZP much greater than apomorphine greater than WB 4010 greater than ketanserin approximately spiperone. The preliminary data suggest that the agent is highly selective for the CNS D-1 receptor.

Animals↗

PubMed1975

1,5-ethano-2,3,4,5-tetrahydro-1H-3-benzazepines.

1,5-Ethano-2,3,4,5-tetrahydro-1H-3-benzazepine, from the LiA1H4 reduction of 2-benzyloxy-1,5-ethano-4-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine, was converted to N-alkyl, aralkyl, cycloalkyl, and alkenyl derivatives which were inactive as morphine type analgetics in mice. The LiA1H4 reduction of 2-benzyloxy-1,5-etheno-4-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine gave unstable products from which only the skeletally rearranged dihydro- and tetrahydrobenzo[e]isoindolines, were isolated.

Administration, Oral↗

PubMed1988

A novel class of potential central nervous system agents. 3-Phenyl-2-(1-piperazinyl)-5H-1-benzazepines.

A series of 3-phenyl-2-piperazinyl-5H-1-benzazepines and related compounds were synthesized and evaluated for potential neuroleptic activity. The preparation of these compounds was carried out by 2,3-dichlorination of 3-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-ones with phosphorus pentachloride followed by amination and concurrent dehydrochlorination. Compounds having the 4-chloro or 4-fluoro substituent in the 3-phenyl group were found to possess the neuroleptic-like activity. Among them, 2-(4-methyl-1-piperazinyl)-3-(4-fluorophenyl)-5H-1-benzazepine dihydrochloride (23) was comparable to chlorpromazine in inhibiting exploratory activity, conditioned avoidance response, and self-stimulation response and more potent than chlorpromazine in antagonizing apomorphine-induced emesis. These neuroleptic effects may be based on an antidopaminergic property of the compound. In causing catalepsy or ptosis, however, 23 was weaker than chlorpromazine. Therefore, this ring system is of interest as a novel class of neuroleptics. Some compounds having the 7-chloro or 7-bromo substituent showed potent anticonvulsant effects against maximal seizures induced by electroshock or pentylenetetrazole.

Animals↗

PubMed1988

Evidence for heterogeneity between pre- and postjunctional alpha-2 adrenoceptors using 9-substituted 3-benzazepines.

A series of alpha adrenoceptor antagonists, including both reference compounds and the novel benzazepine antagonists, SK&F 86466 (6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine) and two of its 9-substituted derivatives, SK&F 101253 and SK&F 104078, were tested in vitro for affinity at central and peripheral alpha adrenoceptor subtypes. Peripheral alpha-1 adrenoceptor antagonist potency of these agents, as assessed by the receptor dissociation constant (KB) against norepinephrine-induced contraction in the rabbit aorta, correlated with the Ki value for inhibition of [3H]prazosin binding to central alpha-1 adrenoceptors in rat brain homogenates. Central alpha-2 adrenoceptor affinity, measured as the Ki for inhibition of [3H]rauwolscine binding to rat brain homogenates, correlated well with antagonist activity at peripheral postjunctional alpha-2 adrenoceptors as reflected by the KB against B-HT 920-induced contraction in canine saphenous vein. The 9-substituted benzazepines, SK&F 101253 and SK&F 104078, produce preferential blockade of postjunctional vs. prejunctional alpha-2 adrenoceptors in peripheral models. The high affinity of SK&F 104078 for postjunctional alpha-2 adrenoceptors in the canine saphenous vein was confirmed by its ability to inhibit [3H]rauwolscine binding to postjunctional alpha-2 adrenoceptors in this tissue. The observation that the Ki values for these antagonists against [3H] rauwolscine binding correlate with their KB values at the postjunctional alpha-2 adrenoceptors, rather than those at the prejunctional neuroinhibitory alpha-2 adrenoceptor, suggests a pharmacologic similarity between the postjunctional vascular alpha-2 adrenoceptors and the central [3H]rauwolscine binding site.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed1985

Structural determinants of selective affinity for brain D-1 dopamine receptors within a series of 1-phenyl-1H-3-benzazepine analogues of SK&F 38393 and SCH 23390.

A series of 1-phenyl-1H-3 benzazepine analogues of the D-1 agonist SK&F 38393 and of the D-1 antagonist SCH 23390 were compared for their relative abilities to displace the binding of [3H]piflutixol and [3H]spiperone to striatal D-1 and D-2 receptors respectively. The benzazepine analogues varied in substitutions at the 3- and 7-positions which distinguish SK & 38393 from SCH 23390. Substitutions at these positions critically influenced affinity for D-1 receptors over a 2000-fold range but influenced affinity for D-2 receptors over only a 30-fold range. 7-Substituents prominently increased affinity and selectivity for D-1 receptors with a rank order of Br = Cl much greater than CH3 greater than H greater than OH. 3-Methylation had a less marked and less selective action to increase affinity for D-1 receptors. Such structural relationships may aid the definition of the topography of brain D-1 receptors and the development of improved selective agents.

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

PubMed1992

A study on the contribution of the 1-phenyl substituent to the molecular electrostatic potentials of some benzazepines in relation to selective dopamine D-1 receptor activity.

The molecular electrostatic potentials for a selective dopamine D-1 receptor antagonist, 7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-methylbenzazepine (SCH 23390 (1], and a selective dopamine D-1 receptor agonist, 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SK&F 38393 (2], have been calculated in order to obtain an understanding of the nature of the interactions between the phenyl ring and the receptor. Analogues of 1 with conformationally constrained phenyl rings have also been studied. Based on this study, the conclusion is drawn that an important part of the interaction between the phenyl ring in the benzazepines and the receptor is due to electrostatic forces, and that the phenyl ring interacts with the same receptor site as the oxygen atom of the 8-hydroxy group.

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

PubMed1990

Conformational analysis and structure-activity relationships of selective dopamine D-1 receptor agonists and antagonists of the benzazepine series.

Comprehensive conformational analysis using molecular mechanics calculations (MM2(85)) has been carried out for the potent and selective dopamine D-1 receptor agonist 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1; SK&F 38393), the antagonist 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (8; SCH 23390), and several analogues, including conformationally constrained ones. Calculated conformational energies have been related to pharmacological and biochemical data in an attempt to identify the biologically active conformations of 1 and 8. It is concluded that the most probable receptor-bound conformation in both cases is a chair conformation with an equatorial phenyl ring and for 8 an equatorial N-methyl group. It is suggested that the orientation of the phenyl ring in the receptor-bound molecule does not deviate in terms of dihedral angles by more than about 30 degrees from the preferred phenyl group rotamer in which the planes of two aromatic rings are essentially orthogonal.

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

PubMed1992

6-Hydroxy-3-n-propyl-2,3,4,5-tetrahydro-1H-3-benzazepine and analogs: new centrally acting 5-HT1A receptor agonists.

The ring-closed phenylethylamine analogue 6-hydroxy-3-n-propyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1) is a 5-HT1A receptor agonist of moderate potency, according to both in vivo biochemical data and in vitro binding data. The active compounds of this series also induce the 5-HT behavioral syndrome. Molecular modeling studies were performed with molecular mechanics calculations, and a tentative explanation for the relatively low potency of these serotonergic benzazepines is provided.

Animals↗

PubMed1991

(+/-)-3-Allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepin, a new high-affinity D1 dopamine receptor ligand: synthesis and structure-activity relationship.

The 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines form a series of compounds having a high affinity at the D1 dopamine receptor. The 6-chloro derivative has been previously shown to have enhanced affinity, selectivity, and agonist activity. In an attempt to study the effect of substitution of a 6-bromo group in place of the 6-chloro, we have synthesized a series of compounds and evaluated them for their affinity for the D1 receptor. The results show that the 6-bromo derivatives have virtually identical affinities to their 6-chloro counterparts, a finding similar to that found in the D1 antagonist 7-halo-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine series. From the present work, 3-allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepi ne (6-Br-APB) has been identified as a suitable candidate for further in vivo studies and resolution into its active and inactive enantiomers.

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