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PubMed1995

Differential anti-parkinsonian effects of benzazepine D1 dopamine agonists with varying efficacies in the MPTP-treated common marmoset.

In common marmosets systemically treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), the behavioural effects of benzazepine D1 dopamine (DA) agonists with full/supramaximal (SKF 80723 and SKF 82958), partial (SKF 38393, SKF 75670 and SKF 83565) and no efficacies (SKF 83959) in stimulating adenylate cyclase (AC) activity were investigated. The benzazepine derivatives, with the exception of SKF 82958 (8 fold D1 DA receptor selectivity), demonstrated high D1 DA receptor affinity and selectivity (approximately 100 fold or more) in rat striatal homogenates. Administration of MPTP in marmosets induced locomotor hypoactivity, rigidity and motor disability. SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine) and SKF 75670 (3-CH3 analogue) further reduced locomotor activity (by -70 to -80%) and increased motor disability (by +22 to +67%) in these animals. SKF 83565 (6-Cl, 3-CH3, 3'-Cl analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue) had only a slight effect on locomotor activity but decreased motor disability at high doses (-46 to -60%). In contrast, SKF 83959 (6-Cl, 3-CH3, 3'-CH3 analogue) and SKF 80723 (6-Br analogue) produced pronounced increases in locomotion (6-10 fold) and a reversal in motor disability (by -64 to -77%). Oral activity, consisting largely of abnormal, 'dyskinetic' tongue protrusions and vacuous chews, was increased in animals treated with SKF 38393, SKF 83565, SKF 82958 and more especially with SKF 80723 and SKF 83959. Grooming was increased with SKF 82958 and more especially with SKF 80723 and SKF 83959. In contrast, quinpirole (D2 DA agonist), reversed the MPTP-induced motor deficits in the marmoset, with no effect on grooming and oral activity. The present findings further demonstrate the antiparkinsonian actions of some D1 DA agonists in MPTP-treated primates. However, in general the behavioural effects of benzazepines failed to correlate with either their D1 DA receptor affinity/selectivity or their efficacy in stimulating adenylate cyclase (AC) activity. These observations further implicate a behavioural role for D1 DA receptors uncoupled to AC and/or a role for extrastriatal D1 DA receptors in mediating the behavioural response to D1 DA agonists.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

Selective dopamine antagonist pretreatment on the antiparkinsonian effects of benzazepine D1 dopamine agonists in rodent and primate models of Parkinson's disease--the differential effects of D1 dopamine antagonists in the primate.

In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle, pretreatment with the D1 DA antagonists, SCH 23390 (7-chloro-8-hydroxy-2,3,4,5-tetrahydro-3-methyl-1-phenyl-1H-3-benzazepin e) and A66359 (1- 2-bromo-4,5-dimethoxybenzyl]-7-hydroxy-6-methoxy-2-methyl- 1,2,3,4 tetrahydroisoquinoline), but not the D2 DA antagonist raclopride inhibited the contralateral circling induced by the benzazepine D1 DA agonists SKF 38393 (7-H, 3-H analogue of SCH 23390), SKF 80723 (7-H, 3-H, 6-Br analogue) and SKF 83959 (7-H, 6-Cl, 3'-CH3 analogue). In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated common marmosets, administration of SKF 80723 and SKF 83959 increased locomotor activity and reversed the motor disability. Grooming and oral activities were also increased. Pretreatment with SCH 23390 and A66359 inhibited all the behavioural changes induced by both D1 DA agonists. In general, higher doses of A66359 and more especially SCH 23390 were needed to inhibit SKF 83959 and SKF 80723 induced increases in oral activity and grooming than locomotor activity. Raclopride pretreatment did not affect SKF 83959 and SKF 80723 induced oral activity and grooming, though it reduced the duration of the locomotor changes induced by the D1 DA agonists. These findings demonstrate that the behavioural effects of benzazepine D1 DA agonists in the 6-OHDA lesioned rat and MPTP-treated marmoset are mediated by D1 DA receptor sites, although in the primate, stimulation of D2 DA receptors by endogenous DA may be necessary in facilitating the antiparkinsonian effects of D1 DA agonists. The differential sensitivities of locomotor/motor disability and oral/grooming behaviours to antagonism by D1 DA antagonists may indicate the involvement of multiple D1 DA receptor subtypes in mediating benzazepine D1 DA agonist induced behaviours in the MPTP-treated marmoset.

Analysis of Variance↗
PubMed2004

Synthesis and structure/NMDA receptor affinity relationships of 1-substituted tetrahydro-3-benzazepines.

A novel synthesis of 1-substituted tetrahydro-1H-3-benzazepines 4 is described. Starting with (2-bromophenyl)acetaldehyde acetal 5, the nitrostyrene 9 was prepared in three steps allowing the addition of various nucleophiles to yield the nitroacetals 10. The one-pot Zn/HCl reductive cyclization of the nitroacetals 10 provided the 3-benzazepines 4, which were investigated for their affinity to the phencyclidine binding site of the NMDA receptor. A one-atomic spacer between the 3-benzazepine system and the phenyl residue in position 1 seems to be favorable for high NMDA receptor binding. In this series the benzazepine 4l substituted with the conformationally restricted and H-bond accepting acetanilide substituent in position 1 displays the highest NMDA receptor affinity (K(i)=89 nM).

Animals↗
PubMed1995

(+/-)-(N-alkylamino)benzazepine analogs: novel dopamine D1 receptor antagonists.

(+/-)-(N-Alkylamino)benzazepine analogs were prepared as novel dopamine D1 receptor antagonists to further elucidate the role of these receptor subtypes in the pharmacology and toxicology of cocaine. In the first series of compounds, (+/-)-7-chloro-8-hydroxy-3- [6-(N,N-dimethylamino)-hexyl]-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepi ne (15) showed the highest affinity (Ki = 49.3 nM) and subtype-selectivity for dopamine D1 over dopamine D2, 5-HT2a, and 5-HT2c receptors. Compounds 7a [(+/-)-7-Chloro-8-hydroxy-3-[4-(N,N-dimethylamino)butyl]-1-phenyl- 2,3,4,5-tetrahydro-1H-3-benzazepine], 11 [(+/-)-7-chloro-8-hydroxy-3-[6-[(N,N-dimethylamino)hexyl]-1- phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-cyanoborane], and 15 were moderately potent dopamine D1 receptor antagonists as evidenced by their ability to block dopamine-stimulated adenylyl cyclase activity in rat caudate (predicted Ki values = 60, 34, and 21 nM, respectively). Compound 7a appears to be unique in that, despite its relatively potent inhibition of dopamine stimulated adenylyl cyclase, it demonstrated relatively weak binding affinity at the dopamine D1 receptors (Ki = 811 nM). Unlike previously reported N-alkylbenzazepines, where a significant loss in dopamine D1 receptor binding affinity was observed when successive increases in the alkyl side chain size at the benzazepine nitrogen were made, several of these novel N-alkylamino analogs demonstrated high-affinity binding with an optimal chain length of six carbons. This initial series of compounds appears to be identifying another binding domain on the dopamine D1 receptor protein that has not previously been characterized and that accepts an amino function. Further, these compounds may serve as templates for the design of peripherally active dopamine D1 receptor antagonists.

Animals↗
PubMed2004

Orally active CCR5 antagonists as anti-HIV-1 agents: synthesis and biological activity of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivatives containing a tertiary amine moiety.

The search for orally active CCR5 antagonists was performed by chemical modification of the 1-benzothiepine 1,1-dioxide 3 and 1-benzazepine 4 lead compounds containing a tertiary amine moiety. Replacement of methyl group with a 2-(C(2-4) alkoxy)ethoxy group at the 4-position on the 7-phenyl group of the 1-benzothiepine ring resulted in both enhanced activity and significant improvement in the pharmacokinetic properties upon oral administration in rats. Introduction of C(2-4) alkyl, phenyl or (hetero)arylmethyl groups as the 1-substituent on the 1-benzazepine ring together with the 2-(butoxy)ethoxy group led to further increase of activity. Among the 1-benzazepine derivatives, the isobutyl (6i), benzyl (6o) or 1-methylpyrazol-4-ylmethyl (6s) compounds were found to exhibit highly potent inhibitory effects, equivalent to the injectable CCR5 antagonist 1, in the HIV-1 envelope-mediated membrane fusion assay. In particular, compound 6s showed the most potent CCR5 antagonistic activity (IC(50)=2.7 nM) and inhibitory effect (IC(50)=1.2 nM) on membrane fusion, together with good pharmacokinetic properties in rats. The synthesis of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivatives and their biological activity are described.

Administration, Oral↗
PubMed1997

Noncompetitive NMDA antagonists: a novel synthesis of 1-phenyltetrahydro-3-benzazepines.

The key step in the synthesis of the pharmacologically interesting 1-phenyltetrahydro-3-benzazepine skeleton is the Michael addition of (2-lithiophenyl)acetaldehyde acetals, which are generated in situ upon treatment of the bromo acetals 5a,b with n-butyllithium, to beta-nitrostyrene (6). The reductive ring closure of the nitro acetals 7a,b succeeded with zinc dust and hydrochloric acid to give the 3-benzazepines 11a,b in good yields. The unsubstituted 3-benzazepine 11a showed a considerable affinity for the phencyclidine binding site of the NMDA receptor (Ki = 6.41 microM), whereas donor substituents in the aryl moiety (11b,c) reduce the affinity for the NMDA receptor.

Benzazepines↗
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↗
PubMed1999

1,3-Disubstituted benzazepines as neuropeptide Y Y1 receptor antagonists.

A novel class of potent and selective non-peptide neuropeptide Y (NPY) Y1 receptor antagonists, having benzazepine nuclei, have been designed, synthesized, and evaluated for activity. Through a blind screening we found the compound 1-N-(3-(N'-(tert-butoxycarbonyl)amino)benzyl)-7-methoxy-(3-(3)-methyl ureido)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (9: IC50 = 1.6 microM). Chemical modifications of 9 gave a potent NPY Y1 antagonist 3-(N-(4-hydroxyphenyl)-N'-methylguanidino)-1-N-(3-(N'-(tert-butoxy carbonyl)amino)benzyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (14c: IC5(0=43 nM), which had no affinity for NPY Y2 and Y5 receptors.

Benzazepines↗
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↗
PubMed1982

Dopaminergic activity of substituted 6-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines.

6-Chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines were synthesized and evaluated as agonists of central and peripheral dopamine receptors. These benzazepines were prepared by cyclization of certain amino alcohols followed by demethylation of the 7,8-dimethoxy groups of the precursors to the 7,8-catecholic moiety. Preliminary evidence of dopaminergic activity was determined in anesthetized dogs by measuring the effects on renal blood flow and calculating the accompanying changes in renal vascular resistance. The most potent compounds contained an hydroxyl group on the 1-phenyl group or were substituted at the 3' position with a chloro, methyl, or trifluoromethyl group. Evidence for central dopaminergic activity was obtained by measuring rotational effects in rats lesioned in the substantia nigra and also in an in vitro assay which measured stimulation of rat striatal adenylate cyclase. The compounds with the best central dopaminergic activity were generally the benzazepines which were the most lipophilic, were substituted on the 3' position of th 1-phenyl group, and contained either a 3-N-methyl or 3-N-allyl group.

Animals↗
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↗
PubMed1996

Orally active, nonpeptide vasopressin V2 receptor antagonists: a novel series of 1-[4-(benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepines and related compounds.

This paper describes a novel series of nonpeptide vasopressin V2 receptor antagonists. It has been demonstrated that the 1-[4-(benzoylamino)benzoyl]-2,3,4,5-1H-benzazepines and 1-[4-(benzoylamino)benzoyl]-2,3,4,5-1H-1,5-benzodiazepines show a high affinity for V2 (and V1a) receptors. Among the 1-[4-(benzoylamino)benzoyl]-2,3,4,5-1H-benzazepine series, compounds with an alkylamino group on the benzazepine ring have been shown to have oral activity. A lipophilic group at the ortho position on the terminal benzoyl ring is important for both high V2 receptor affinity and oral activity. On the basis of these favorable properties, clinical testing of 31b has begun for use as an oral and iv aquaretic agent.

Administration, Oral↗
PubMed1998

d-Fused [1]benzazepines with selective in vitro antitumor activity: synthesis and structure-activity relationships.

The synthesis of novel quinolino[3,2-d][1]benzazepines and pyrido[3,2-d][1]benzazepines is described. The in vitro antitumor activity of the compounds has been tested in the antitumor screening of the National Cancer Institute (NCI). Several 2,4-diarylpyrido[3, 2-d][1]benzazepin-6-ones and -thiones turned out to exhibit considerable cytotoxicity for tumor cells. For studies of SAR within these series, substituents were introduced into the aromatic rings of the parent systems. Compounds from the thiolactam series tended to show higher potency than the corresponding lactams. Prominent compounds with noteworthy activity and remarkable selectivity for renal cancer cell lines are the lactams 10c, 10g, and 10h and the corresponding thiolactams 11c, 11g, and 11h. Methylation of the azepine nitrogen leads to complete loss of activity, whereas annelation of a triazolo ring at the lactam site or transformation of the thiolactam function to a thiolactim ether results in decreased antitumor activity and selectivity. Consequently, the secondary lactam or thiolactam structure of the seven-membered ring has to be regarded as essential for selective antitumor activity.

Antineoplastic Agents↗
PubMed1995

In vivo microdialysis evidence for transient dopamine release by benzazepines in rat striatum.

The effects of benzazepine derivatives on extracellular levels of dopamine (DA) and L-3,4-dihydroxy-phenylacetic acid (DOPAC) in the dorsal striatum of freely moving rats were studied using in vivo microdialysis. Direct injection of SKF-38393 (0.5 or 1.5 micrograms/0.5 microliter), a selective D1 receptor agonist, into the striatum through a cannula secured alongside a microdialysis probe produced a rapid dose-dependent transient increase in striatal DA efflux and a more gradual reduction in efflux of DOPAC. The rapid increase in DA efflux was not affected by infusion of tetrodotoxin (TTX; 2 microM) or Ca(2+)-free Ringer's solution and occurred after either enantiomer of SKF-38393. A TTX-insensitive increase in DA level similar to that induced by SKF-38393 was also seen after other benzazepines acting as agonists (SKF-75670 and SKF-82958, each 1.5 micrograms in 0.5 microliter) and antagonists (SCH-23390, 1.5 micrograms in 0.5 microliter) at the D1 receptor and after (+)-amphetamine. These effects were inhibited by infusion of nomifensine (100 microM). It is concluded that the transient increases in striatal DA efflux seen after intrastriatal injection of SKF-38393 and other benzazepines are not mediated by presynaptic D1 receptors but by an amphetamine-like action on the dopamine transporter.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2002

Classic D1 dopamine receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) directly inhibits G protein-coupled inwardly rectifying potassium channels.

R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) is a widely used, highly selective antagonist of D1 dopamine receptors. While investigating the crosstalk between D1 and D3 dopamine receptor signaling pathways, we discovered that in addition to being a D1 receptor antagonist, SCH23390 and related compounds inhibit G protein-coupled inwardly rectifying potassium (GIRK) channels. We present evidence that SCH23390 blocks endogenous GIRK currents induced by either somatostatin or D3 dopamine receptors in AtT-20 cells (IC50, 268 nM). The inhibition is receptor-independent because constitutive GIRK currents in Chinese hamster ovary cells expressing only GIRK channels are also blocked by SCH23390. The inhibition of GIRK channels is somewhat selective because members of the closely related Kir2.0 family of inwardly rectifying potassium channels, as well as various endogenous cationic currents present in AtT-20 cells, are not affected. In addition, in current clamp recordings, SCH23390 can depolarize the membrane potential and induce AtT-20 cells to fire action potentials, indicating potential physiological significance of the GIRK channel inhibition. To identify the chemical features that contribute to GIRK channel block, we tested several structurally related compounds [SKF38393, R-(+)-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (nor-methyl-SCH23390), and R-(+)-2,3,4,5-tetrahydro-8-iodo-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hydrochloride (iodo-SCH23390)], and our results indicate that the halide atom is critical for blocking GIRK channels. Taken together, our results suggest that SCH23390 and related compounds might provide the basis for designing novel GIRK channel-selective blockers. Perhaps more importantly, some studies that have exclusively used SCH23390 to probe D1 receptor function or as a diagnostic of D1 receptor involvement may need to be reevaluated in light of these results.

Animals↗