(±)-(N-alkylamino)benzazepine analogs

Novel dopamine D1 receptor antagonists

Jamshed H. Shah, Sari E Izenwasser, Beth Geter-Douglass, Jeffrey M. Witkin, Amy Hauck Newman

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

(±)-(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-benzazepine (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.

Original languageEnglish
Pages (from-to)4284-4293
Number of pages10
JournalJournal of Medicinal Chemistry
Volume38
Issue number21
StatePublished - Dec 1 1995
Externally publishedYes

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Benzazepines
Dopamine D1 Receptors
Dopamine Antagonists
Dopamine
Adenylyl Cyclases
Receptor, Serotonin, 5-HT2C
Chain length
Cocaine
Toxicology
Rats
Nitrogen
Carbon
Pharmacology

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Shah, J. H., Izenwasser, S. E., Geter-Douglass, B., Witkin, J. M., & Newman, A. H. (1995). (±)-(N-alkylamino)benzazepine analogs: Novel dopamine D1 receptor antagonists. Journal of Medicinal Chemistry, 38(21), 4284-4293.

(±)-(N-alkylamino)benzazepine analogs : Novel dopamine D1 receptor antagonists. / Shah, Jamshed H.; Izenwasser, Sari E; Geter-Douglass, Beth; Witkin, Jeffrey M.; Newman, Amy Hauck.

In: Journal of Medicinal Chemistry, Vol. 38, No. 21, 01.12.1995, p. 4284-4293.

Research output: Contribution to journalArticle

Shah, JH, Izenwasser, SE, Geter-Douglass, B, Witkin, JM & Newman, AH 1995, '(±)-(N-alkylamino)benzazepine analogs: Novel dopamine D1 receptor antagonists', Journal of Medicinal Chemistry, vol. 38, no. 21, pp. 4284-4293.
Shah, Jamshed H. ; Izenwasser, Sari E ; Geter-Douglass, Beth ; Witkin, Jeffrey M. ; Newman, Amy Hauck. / (±)-(N-alkylamino)benzazepine analogs : Novel dopamine D1 receptor antagonists. In: Journal of Medicinal Chemistry. 1995 ; Vol. 38, No. 21. pp. 4284-4293.
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abstract = "(±)-(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-benzazepine (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.",
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N2 - (±)-(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-benzazepine (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.

AB - (±)-(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-benzazepine (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.

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