The effects of SB 216469, an antagonist which discriminates between the α(1A)-adrenoceptor and the human prostatic α1-adrenoceptor

R. Chess-Williams, C. R. Chapple, F. Verfurth, A. J. Noble, C. J. Couldwell, M. C. Michel

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Abstract

1 The affinity of the α1-adrenoceptor antagonist SB 216469 (also known as REC 15/2739) has been determined at native and cloned α1-adrenoceptor subtypes by radioligand binding and at functional α1-adrenoceptor subtypes in isolated tissues. 2 In radioligand binding studies with [3H]-prazosin, SB 216469 had a high affinity at the α(1A)-adrenoceptors of the rat cerebral cortex and kidney (9.5-9.8) but a lower affinity at the α(1B)-adrenoceptors of the rat spleen and liver (7.7-8.2). 3 At cloned rat α1-adrenoceptor subtypes transiently expressed in COS-1 cells and also at cloned human α1-adrenoceptor subtypes stably transfected in Rat-1 cells, SB 216469 exhibited a high affinity at the α(1a)-adrenoceptors (9.6-10.4) with a significantly lower affinity at the α(1b)-adrenoceptor (8.0-8.4) and an intermediate affinity at the m-adrenoceptor (8.7-9.2). 4 At functional α1-adrenoceptors, SB 216469 had a similar pharmacological profile, with a high affinity at the α(1A)-adrenoceptors of the rat vas deferens and anococcygeus muscle (pA2 = 9.5-10.0), a low affinity at the α(1B)-adrenoceptors of the rat spleen (6.7) and guinea-pig aorta (8.0), and an intermediate affinity at the α(1D)-adrenoceptors of the rat aorta (8.8). 5 Several recent studies have concluded that the α1-adrenoceptor present in the human prostate has the pharmacological characteristics of the α(1A)-adrenoceptor subtype. However, the affinity of SB 216469 at human prostatic α1-adrenoceptors (pA2 = 8.1) determined in isolated tissue strips, was significantly lower than the values obtained at either the cloned α(1a)-adrenoceptors (human, rat, bovine) or the native α(1A)-adrenoceptors in radioligand binding and functional studies in the rat. 6 Our results with SB 216469, therefore, suggest that the α1-adrenoceptor mediating contractile responses of the human prostate has properties which distinguish it from the cloned α1-adrenoceptor or native α(1A)-adrenoceptor. Since it has previously been shown that the receptor is not the α(1B)- or α(1D)- adrenoceptor, the functional α1-adrenoceptor of the human prostate may represent a novel receptor with properties which differ from any of the α1-adrenoceptors currently defined by pharmacological means.

Original languageEnglish
Pages (from-to)1093-1100
Number of pages8
JournalBritish Journal of Pharmacology
Volume119
Issue number6
DOIs
Publication statusPublished - 1 Jan 1996
Externally publishedYes

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Adrenergic Receptors
Prostate
Pharmacology
Aorta
Spleen
Vas Deferens

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Chess-Williams, R. ; Chapple, C. R. ; Verfurth, F. ; Noble, A. J. ; Couldwell, C. J. ; Michel, M. C. / The effects of SB 216469, an antagonist which discriminates between the α(1A)-adrenoceptor and the human prostatic α1-adrenoceptor. In: British Journal of Pharmacology. 1996 ; Vol. 119, No. 6. pp. 1093-1100.
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abstract = "1 The affinity of the α1-adrenoceptor antagonist SB 216469 (also known as REC 15/2739) has been determined at native and cloned α1-adrenoceptor subtypes by radioligand binding and at functional α1-adrenoceptor subtypes in isolated tissues. 2 In radioligand binding studies with [3H]-prazosin, SB 216469 had a high affinity at the α(1A)-adrenoceptors of the rat cerebral cortex and kidney (9.5-9.8) but a lower affinity at the α(1B)-adrenoceptors of the rat spleen and liver (7.7-8.2). 3 At cloned rat α1-adrenoceptor subtypes transiently expressed in COS-1 cells and also at cloned human α1-adrenoceptor subtypes stably transfected in Rat-1 cells, SB 216469 exhibited a high affinity at the α(1a)-adrenoceptors (9.6-10.4) with a significantly lower affinity at the α(1b)-adrenoceptor (8.0-8.4) and an intermediate affinity at the m-adrenoceptor (8.7-9.2). 4 At functional α1-adrenoceptors, SB 216469 had a similar pharmacological profile, with a high affinity at the α(1A)-adrenoceptors of the rat vas deferens and anococcygeus muscle (pA2 = 9.5-10.0), a low affinity at the α(1B)-adrenoceptors of the rat spleen (6.7) and guinea-pig aorta (8.0), and an intermediate affinity at the α(1D)-adrenoceptors of the rat aorta (8.8). 5 Several recent studies have concluded that the α1-adrenoceptor present in the human prostate has the pharmacological characteristics of the α(1A)-adrenoceptor subtype. However, the affinity of SB 216469 at human prostatic α1-adrenoceptors (pA2 = 8.1) determined in isolated tissue strips, was significantly lower than the values obtained at either the cloned α(1a)-adrenoceptors (human, rat, bovine) or the native α(1A)-adrenoceptors in radioligand binding and functional studies in the rat. 6 Our results with SB 216469, therefore, suggest that the α1-adrenoceptor mediating contractile responses of the human prostate has properties which distinguish it from the cloned α1-adrenoceptor or native α(1A)-adrenoceptor. Since it has previously been shown that the receptor is not the α(1B)- or α(1D)- adrenoceptor, the functional α1-adrenoceptor of the human prostate may represent a novel receptor with properties which differ from any of the α1-adrenoceptors currently defined by pharmacological means.",
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The effects of SB 216469, an antagonist which discriminates between the α(1A)-adrenoceptor and the human prostatic α1-adrenoceptor. / Chess-Williams, R.; Chapple, C. R.; Verfurth, F.; Noble, A. J.; Couldwell, C. J.; Michel, M. C.

In: British Journal of Pharmacology, Vol. 119, No. 6, 01.01.1996, p. 1093-1100.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - The effects of SB 216469, an antagonist which discriminates between the α(1A)-adrenoceptor and the human prostatic α1-adrenoceptor

AU - Chess-Williams, R.

AU - Chapple, C. R.

AU - Verfurth, F.

AU - Noble, A. J.

AU - Couldwell, C. J.

AU - Michel, M. C.

PY - 1996/1/1

Y1 - 1996/1/1

N2 - 1 The affinity of the α1-adrenoceptor antagonist SB 216469 (also known as REC 15/2739) has been determined at native and cloned α1-adrenoceptor subtypes by radioligand binding and at functional α1-adrenoceptor subtypes in isolated tissues. 2 In radioligand binding studies with [3H]-prazosin, SB 216469 had a high affinity at the α(1A)-adrenoceptors of the rat cerebral cortex and kidney (9.5-9.8) but a lower affinity at the α(1B)-adrenoceptors of the rat spleen and liver (7.7-8.2). 3 At cloned rat α1-adrenoceptor subtypes transiently expressed in COS-1 cells and also at cloned human α1-adrenoceptor subtypes stably transfected in Rat-1 cells, SB 216469 exhibited a high affinity at the α(1a)-adrenoceptors (9.6-10.4) with a significantly lower affinity at the α(1b)-adrenoceptor (8.0-8.4) and an intermediate affinity at the m-adrenoceptor (8.7-9.2). 4 At functional α1-adrenoceptors, SB 216469 had a similar pharmacological profile, with a high affinity at the α(1A)-adrenoceptors of the rat vas deferens and anococcygeus muscle (pA2 = 9.5-10.0), a low affinity at the α(1B)-adrenoceptors of the rat spleen (6.7) and guinea-pig aorta (8.0), and an intermediate affinity at the α(1D)-adrenoceptors of the rat aorta (8.8). 5 Several recent studies have concluded that the α1-adrenoceptor present in the human prostate has the pharmacological characteristics of the α(1A)-adrenoceptor subtype. However, the affinity of SB 216469 at human prostatic α1-adrenoceptors (pA2 = 8.1) determined in isolated tissue strips, was significantly lower than the values obtained at either the cloned α(1a)-adrenoceptors (human, rat, bovine) or the native α(1A)-adrenoceptors in radioligand binding and functional studies in the rat. 6 Our results with SB 216469, therefore, suggest that the α1-adrenoceptor mediating contractile responses of the human prostate has properties which distinguish it from the cloned α1-adrenoceptor or native α(1A)-adrenoceptor. Since it has previously been shown that the receptor is not the α(1B)- or α(1D)- adrenoceptor, the functional α1-adrenoceptor of the human prostate may represent a novel receptor with properties which differ from any of the α1-adrenoceptors currently defined by pharmacological means.

AB - 1 The affinity of the α1-adrenoceptor antagonist SB 216469 (also known as REC 15/2739) has been determined at native and cloned α1-adrenoceptor subtypes by radioligand binding and at functional α1-adrenoceptor subtypes in isolated tissues. 2 In radioligand binding studies with [3H]-prazosin, SB 216469 had a high affinity at the α(1A)-adrenoceptors of the rat cerebral cortex and kidney (9.5-9.8) but a lower affinity at the α(1B)-adrenoceptors of the rat spleen and liver (7.7-8.2). 3 At cloned rat α1-adrenoceptor subtypes transiently expressed in COS-1 cells and also at cloned human α1-adrenoceptor subtypes stably transfected in Rat-1 cells, SB 216469 exhibited a high affinity at the α(1a)-adrenoceptors (9.6-10.4) with a significantly lower affinity at the α(1b)-adrenoceptor (8.0-8.4) and an intermediate affinity at the m-adrenoceptor (8.7-9.2). 4 At functional α1-adrenoceptors, SB 216469 had a similar pharmacological profile, with a high affinity at the α(1A)-adrenoceptors of the rat vas deferens and anococcygeus muscle (pA2 = 9.5-10.0), a low affinity at the α(1B)-adrenoceptors of the rat spleen (6.7) and guinea-pig aorta (8.0), and an intermediate affinity at the α(1D)-adrenoceptors of the rat aorta (8.8). 5 Several recent studies have concluded that the α1-adrenoceptor present in the human prostate has the pharmacological characteristics of the α(1A)-adrenoceptor subtype. However, the affinity of SB 216469 at human prostatic α1-adrenoceptors (pA2 = 8.1) determined in isolated tissue strips, was significantly lower than the values obtained at either the cloned α(1a)-adrenoceptors (human, rat, bovine) or the native α(1A)-adrenoceptors in radioligand binding and functional studies in the rat. 6 Our results with SB 216469, therefore, suggest that the α1-adrenoceptor mediating contractile responses of the human prostate has properties which distinguish it from the cloned α1-adrenoceptor or native α(1A)-adrenoceptor. Since it has previously been shown that the receptor is not the α(1B)- or α(1D)- adrenoceptor, the functional α1-adrenoceptor of the human prostate may represent a novel receptor with properties which differ from any of the α1-adrenoceptors currently defined by pharmacological means.

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