A Structure-Activity Relationship Study of Benzylic Modifications of 4-[1-(1-Naphthyl)ethyl]-1H-imidazoles on α1- and α2-Adrenergic Receptors

Seoung Soo Hong, Karl J. Romstedt, Dennis R. Feller, Fu Lian Hsu, Thomas L. Cupps, Robert A. Lyon, Duane Miller

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The naphthalene analog of medetomidine (1), 4-[1-(1-naphthyl)ethyl]-1H-imidazole (2), is a highly potent, selective α2-adrenoceptor agonist. We have initiated a structure-activity relationship study of the replacement of the methyl group on the carbon bridge between the naphthalene and imidazole rings of 2 with a hydrogen, hydroxy, methoxy, carbonyl, or trifluoromethyl group and compared their biological activities with medetomidine 1 and the optical isomers of 2. Analogs of 2 were antagonists of α2A-adrenoceptor-mediated human platelet aggregation and agonists on α1- and α2-adrenoceptors in guinea pig ileum. The rank order and potencies of these analogs on platelets (α2A-subtype) and guinea pig ileum (α1-subtype) were nearly the same, whereas racemic and S-(+)-2, desmethyl, and hydroxy analogs were potent agonists on α2-adrenoceptors in guinea pig ileum. With the exception of the desmethyl analog 5, none of the other analogs were as potent as the parent drug 2 on α2A- (human platelets), α1- (guinea pig ileum), or α2- (guinea pig ileum) adrenergic receptor systems. As with analog 2, the desmethyl- and methoxy-substituted analogs retained a greater α21-selectivity in both functional (agonist activity) and biochemical (receptor displacement) studies. Receptor binding studies indicate that S-(+)-2 possessed greater affinity than the R-(-)-isomer on both α1- and α2-adrenoceptors in rat brain. In addition, R-(-)-2 did not show agonist activity in α2-adrenoceptors of guinea pig ileum and was 10-fold more potent than S-(+)-2 as an antagonist of α2A-adrenoceptors in human platelets. Thus, the nature of the substituent and the chirality at the carbon bridge between the naphthalene and imidazole rings play an important role in maintaining potent α2-adrenoceptor activity and high α21-selectivity within the 4-substituted imidazole class.

Original languageEnglish (US)
Pages (from-to)2328-2333
Number of pages6
JournalJournal of Medicinal Chemistry
Volume37
Issue number15
DOIs
StatePublished - Jul 1 1994

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Structure-Activity Relationship
Adrenergic Receptors
Ileum
Guinea Pigs
Medetomidine
Blood Platelets
Carbon
4-(1-(1-naphthyl)ethyl)imidazole
Platelet Aggregation
Hydrogen
Brain
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

A Structure-Activity Relationship Study of Benzylic Modifications of 4-[1-(1-Naphthyl)ethyl]-1H-imidazoles on α1- and α2-Adrenergic Receptors. / Hong, Seoung Soo; Romstedt, Karl J.; Feller, Dennis R.; Hsu, Fu Lian; Cupps, Thomas L.; Lyon, Robert A.; Miller, Duane.

In: Journal of Medicinal Chemistry, Vol. 37, No. 15, 01.07.1994, p. 2328-2333.

Research output: Contribution to journalArticle

Hong, Seoung Soo ; Romstedt, Karl J. ; Feller, Dennis R. ; Hsu, Fu Lian ; Cupps, Thomas L. ; Lyon, Robert A. ; Miller, Duane. / A Structure-Activity Relationship Study of Benzylic Modifications of 4-[1-(1-Naphthyl)ethyl]-1H-imidazoles on α1- and α2-Adrenergic Receptors. In: Journal of Medicinal Chemistry. 1994 ; Vol. 37, No. 15. pp. 2328-2333.
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abstract = "The naphthalene analog of medetomidine (1), 4-[1-(1-naphthyl)ethyl]-1H-imidazole (2), is a highly potent, selective α2-adrenoceptor agonist. We have initiated a structure-activity relationship study of the replacement of the methyl group on the carbon bridge between the naphthalene and imidazole rings of 2 with a hydrogen, hydroxy, methoxy, carbonyl, or trifluoromethyl group and compared their biological activities with medetomidine 1 and the optical isomers of 2. Analogs of 2 were antagonists of α2A-adrenoceptor-mediated human platelet aggregation and agonists on α1- and α2-adrenoceptors in guinea pig ileum. The rank order and potencies of these analogs on platelets (α2A-subtype) and guinea pig ileum (α1-subtype) were nearly the same, whereas racemic and S-(+)-2, desmethyl, and hydroxy analogs were potent agonists on α2-adrenoceptors in guinea pig ileum. With the exception of the desmethyl analog 5, none of the other analogs were as potent as the parent drug 2 on α2A- (human platelets), α1- (guinea pig ileum), or α2- (guinea pig ileum) adrenergic receptor systems. As with analog 2, the desmethyl- and methoxy-substituted analogs retained a greater α2/α1-selectivity in both functional (agonist activity) and biochemical (receptor displacement) studies. Receptor binding studies indicate that S-(+)-2 possessed greater affinity than the R-(-)-isomer on both α1- and α2-adrenoceptors in rat brain. In addition, R-(-)-2 did not show agonist activity in α2-adrenoceptors of guinea pig ileum and was 10-fold more potent than S-(+)-2 as an antagonist of α2A-adrenoceptors in human platelets. Thus, the nature of the substituent and the chirality at the carbon bridge between the naphthalene and imidazole rings play an important role in maintaining potent α2-adrenoceptor activity and high α2/α1-selectivity within the 4-substituted imidazole class.",
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AU - Romstedt, Karl J.

AU - Feller, Dennis R.

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N2 - The naphthalene analog of medetomidine (1), 4-[1-(1-naphthyl)ethyl]-1H-imidazole (2), is a highly potent, selective α2-adrenoceptor agonist. We have initiated a structure-activity relationship study of the replacement of the methyl group on the carbon bridge between the naphthalene and imidazole rings of 2 with a hydrogen, hydroxy, methoxy, carbonyl, or trifluoromethyl group and compared their biological activities with medetomidine 1 and the optical isomers of 2. Analogs of 2 were antagonists of α2A-adrenoceptor-mediated human platelet aggregation and agonists on α1- and α2-adrenoceptors in guinea pig ileum. The rank order and potencies of these analogs on platelets (α2A-subtype) and guinea pig ileum (α1-subtype) were nearly the same, whereas racemic and S-(+)-2, desmethyl, and hydroxy analogs were potent agonists on α2-adrenoceptors in guinea pig ileum. With the exception of the desmethyl analog 5, none of the other analogs were as potent as the parent drug 2 on α2A- (human platelets), α1- (guinea pig ileum), or α2- (guinea pig ileum) adrenergic receptor systems. As with analog 2, the desmethyl- and methoxy-substituted analogs retained a greater α2/α1-selectivity in both functional (agonist activity) and biochemical (receptor displacement) studies. Receptor binding studies indicate that S-(+)-2 possessed greater affinity than the R-(-)-isomer on both α1- and α2-adrenoceptors in rat brain. In addition, R-(-)-2 did not show agonist activity in α2-adrenoceptors of guinea pig ileum and was 10-fold more potent than S-(+)-2 as an antagonist of α2A-adrenoceptors in human platelets. Thus, the nature of the substituent and the chirality at the carbon bridge between the naphthalene and imidazole rings play an important role in maintaining potent α2-adrenoceptor activity and high α2/α1-selectivity within the 4-substituted imidazole class.

AB - The naphthalene analog of medetomidine (1), 4-[1-(1-naphthyl)ethyl]-1H-imidazole (2), is a highly potent, selective α2-adrenoceptor agonist. We have initiated a structure-activity relationship study of the replacement of the methyl group on the carbon bridge between the naphthalene and imidazole rings of 2 with a hydrogen, hydroxy, methoxy, carbonyl, or trifluoromethyl group and compared their biological activities with medetomidine 1 and the optical isomers of 2. Analogs of 2 were antagonists of α2A-adrenoceptor-mediated human platelet aggregation and agonists on α1- and α2-adrenoceptors in guinea pig ileum. The rank order and potencies of these analogs on platelets (α2A-subtype) and guinea pig ileum (α1-subtype) were nearly the same, whereas racemic and S-(+)-2, desmethyl, and hydroxy analogs were potent agonists on α2-adrenoceptors in guinea pig ileum. With the exception of the desmethyl analog 5, none of the other analogs were as potent as the parent drug 2 on α2A- (human platelets), α1- (guinea pig ileum), or α2- (guinea pig ileum) adrenergic receptor systems. As with analog 2, the desmethyl- and methoxy-substituted analogs retained a greater α2/α1-selectivity in both functional (agonist activity) and biochemical (receptor displacement) studies. Receptor binding studies indicate that S-(+)-2 possessed greater affinity than the R-(-)-isomer on both α1- and α2-adrenoceptors in rat brain. In addition, R-(-)-2 did not show agonist activity in α2-adrenoceptors of guinea pig ileum and was 10-fold more potent than S-(+)-2 as an antagonist of α2A-adrenoceptors in human platelets. Thus, the nature of the substituent and the chirality at the carbon bridge between the naphthalene and imidazole rings play an important role in maintaining potent α2-adrenoceptor activity and high α2/α1-selectivity within the 4-substituted imidazole class.

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