Pharmacological characterization of A-131701, a novel α1-adrenoceptor antagonist selective for α(1A)- and α(1D)-compared to α(1B)-adrenoceptors

Arthur A. Hancock, Steven A. Buckner, Michael E. Brune, Sweta Katwala, Ivan Milicic, Lynne M. Ireland, Patricia A. Morse, Sheila M. Knepper, Michael D. Meyer, Christopher R. Chapple, Russell Chess-Williams, Amanda J. Noble, Michael Williams, James F. Kerwin

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Abstract

New compounds selective for α(1A)-adrenoceptors in the prostate may offer enhanced efficacy for benign prostatic hyperplasia (BPH), with fewer side effects than current treatment. A-131701 (3-[2-((3aR,9bR)-cis-6-methoxy- 2,3,3a,4,5,9b,hexahydro-[1H]-benz[e]isoindol-2- yl)ethyl]pyridol]3',4':4,5]thieno [3,2-d]pyrimidine-2,4(1H,3H)-dione), from a novel class of benz[e]isolindole pyridothienopyrimidines and pyridothienopyrazines, is selective for α(1a)- and α(1d)-adrenoceptors in radioligand binding studies (0.22 nM at α(1a)-, 0.97 nM at α(1d))- compared to α(1b)-sites (2.5 nM) and in isolated tissue bioassays (pA2 values of 8.9-9.0 for α(1A)-receptors in rat vas deferens or canine prostate strips, 9.1 at α(1D)-sites (rat aorta)), compared to 7.9 at α(1B)-sites (rat spleen). A-131701 also potently blocked radioligand binding to α1- adrenoceptors in canine and human prostatic membranes, but was considerably weaker at α2-adrenoceptors. In isoflurane-anesthetized dogs, A-131701 antagonized epinephrine-induced increases in intraurethral pressure (IUP) with a pseudo-pA2 value of 8.17. In spontaneously hypertensive rats. A- 131701 caused transient decreases in mean arterial blood pressure (MABP) and transient tachycardia. The area under curve (AUC060 min for the hypotensive response was dose-related, with long index value A-131701 of 5.33, suggesting a selectivity of >600-fold comparing IUP to MABP effects. In pentobarbital-anesthetized dogs, A-131701 was more potent in blocking phenylephrine (PHE)-induced increases in IUP (pseudo-pA2 = 8.0), compared to concurrently measured MABP (pseudo-pA2 = 7.2), or sixfold selective. Doses greater than 1,000 nmol/kg i.v. of A-131701 were required to lower blood pressure by 10 mm Hg in these dogs (pED10 = 5.57), indicating a uroselectivity ratio of >250, superior to doxazosin, terazosin, or tamsulosin. Thus, A-131701 is selective for α(1A)- and α(1D)- vs. α(1B)- adrenoceptors in vitro, and prostatic function vs. blood pressure effects in vivo, which may provide therapeutic advantages in the treatment of BPH.

Original languageEnglish
Pages (from-to)140-162
Number of pages23
JournalDrug Development Research
Volume44
Issue number4
DOIs
Publication statusPublished - 1 Aug 1998
Externally publishedYes

Fingerprint

A 131701
Adrenergic Receptors
Pharmacology
Arterial Pressure
Terazosin
tamsulosin
Prostatic Hyperplasia
Dogs
Pressure
Canidae
Prostate
Doxazosin
Blood Pressure
Vas Deferens
Isoflurane
Phenylephrine
Inbred SHR Rats
Pentobarbital
Tachycardia
Biological Assay

Cite this

Hancock, Arthur A. ; Buckner, Steven A. ; Brune, Michael E. ; Katwala, Sweta ; Milicic, Ivan ; Ireland, Lynne M. ; Morse, Patricia A. ; Knepper, Sheila M. ; Meyer, Michael D. ; Chapple, Christopher R. ; Chess-Williams, Russell ; Noble, Amanda J. ; Williams, Michael ; Kerwin, James F. / Pharmacological characterization of A-131701, a novel α1-adrenoceptor antagonist selective for α(1A)- and α(1D)-compared to α(1B)-adrenoceptors. In: Drug Development Research. 1998 ; Vol. 44, No. 4. pp. 140-162.
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title = "Pharmacological characterization of A-131701, a novel α1-adrenoceptor antagonist selective for α(1A)- and α(1D)-compared to α(1B)-adrenoceptors",
abstract = "New compounds selective for α(1A)-adrenoceptors in the prostate may offer enhanced efficacy for benign prostatic hyperplasia (BPH), with fewer side effects than current treatment. A-131701 (3-[2-((3aR,9bR)-cis-6-methoxy- 2,3,3a,4,5,9b,hexahydro-[1H]-benz[e]isoindol-2- yl)ethyl]pyridol]3',4':4,5]thieno [3,2-d]pyrimidine-2,4(1H,3H)-dione), from a novel class of benz[e]isolindole pyridothienopyrimidines and pyridothienopyrazines, is selective for α(1a)- and α(1d)-adrenoceptors in radioligand binding studies (0.22 nM at α(1a)-, 0.97 nM at α(1d))- compared to α(1b)-sites (2.5 nM) and in isolated tissue bioassays (pA2 values of 8.9-9.0 for α(1A)-receptors in rat vas deferens or canine prostate strips, 9.1 at α(1D)-sites (rat aorta)), compared to 7.9 at α(1B)-sites (rat spleen). A-131701 also potently blocked radioligand binding to α1- adrenoceptors in canine and human prostatic membranes, but was considerably weaker at α2-adrenoceptors. In isoflurane-anesthetized dogs, A-131701 antagonized epinephrine-induced increases in intraurethral pressure (IUP) with a pseudo-pA2 value of 8.17. In spontaneously hypertensive rats. A- 131701 caused transient decreases in mean arterial blood pressure (MABP) and transient tachycardia. The area under curve (AUC0 →60 min for the hypotensive response was dose-related, with long index value A-131701 of 5.33, suggesting a selectivity of >600-fold comparing IUP to MABP effects. In pentobarbital-anesthetized dogs, A-131701 was more potent in blocking phenylephrine (PHE)-induced increases in IUP (pseudo-pA2 = 8.0), compared to concurrently measured MABP (pseudo-pA2 = 7.2), or sixfold selective. Doses greater than 1,000 nmol/kg i.v. of A-131701 were required to lower blood pressure by 10 mm Hg in these dogs (pED10 = 5.57), indicating a uroselectivity ratio of >250, superior to doxazosin, terazosin, or tamsulosin. Thus, A-131701 is selective for α(1A)- and α(1D)- vs. α(1B)- adrenoceptors in vitro, and prostatic function vs. blood pressure effects in vivo, which may provide therapeutic advantages in the treatment of BPH.",
author = "Hancock, {Arthur A.} and Buckner, {Steven A.} and Brune, {Michael E.} and Sweta Katwala and Ivan Milicic and Ireland, {Lynne M.} and Morse, {Patricia A.} and Knepper, {Sheila M.} and Meyer, {Michael D.} and Chapple, {Christopher R.} and Russell Chess-Williams and Noble, {Amanda J.} and Michael Williams and Kerwin, {James F.}",
year = "1998",
month = "8",
day = "1",
doi = "10.1002/(SICI)1098-2299(199808)44:4<140::AID-DDR2>3.0.CO;2-R",
language = "English",
volume = "44",
pages = "140--162",
journal = "Drug Development Research",
issn = "0272-4391",
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number = "4",

}

Hancock, AA, Buckner, SA, Brune, ME, Katwala, S, Milicic, I, Ireland, LM, Morse, PA, Knepper, SM, Meyer, MD, Chapple, CR, Chess-Williams, R, Noble, AJ, Williams, M & Kerwin, JF 1998, 'Pharmacological characterization of A-131701, a novel α1-adrenoceptor antagonist selective for α(1A)- and α(1D)-compared to α(1B)-adrenoceptors' Drug Development Research, vol. 44, no. 4, pp. 140-162. https://doi.org/10.1002/(SICI)1098-2299(199808)44:4<140::AID-DDR2>3.0.CO;2-R

Pharmacological characterization of A-131701, a novel α1-adrenoceptor antagonist selective for α(1A)- and α(1D)-compared to α(1B)-adrenoceptors. / Hancock, Arthur A.; Buckner, Steven A.; Brune, Michael E.; Katwala, Sweta; Milicic, Ivan; Ireland, Lynne M.; Morse, Patricia A.; Knepper, Sheila M.; Meyer, Michael D.; Chapple, Christopher R.; Chess-Williams, Russell; Noble, Amanda J.; Williams, Michael; Kerwin, James F.

In: Drug Development Research, Vol. 44, No. 4, 01.08.1998, p. 140-162.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Pharmacological characterization of A-131701, a novel α1-adrenoceptor antagonist selective for α(1A)- and α(1D)-compared to α(1B)-adrenoceptors

AU - Hancock, Arthur A.

AU - Buckner, Steven A.

AU - Brune, Michael E.

AU - Katwala, Sweta

AU - Milicic, Ivan

AU - Ireland, Lynne M.

AU - Morse, Patricia A.

AU - Knepper, Sheila M.

AU - Meyer, Michael D.

AU - Chapple, Christopher R.

AU - Chess-Williams, Russell

AU - Noble, Amanda J.

AU - Williams, Michael

AU - Kerwin, James F.

PY - 1998/8/1

Y1 - 1998/8/1

N2 - New compounds selective for α(1A)-adrenoceptors in the prostate may offer enhanced efficacy for benign prostatic hyperplasia (BPH), with fewer side effects than current treatment. A-131701 (3-[2-((3aR,9bR)-cis-6-methoxy- 2,3,3a,4,5,9b,hexahydro-[1H]-benz[e]isoindol-2- yl)ethyl]pyridol]3',4':4,5]thieno [3,2-d]pyrimidine-2,4(1H,3H)-dione), from a novel class of benz[e]isolindole pyridothienopyrimidines and pyridothienopyrazines, is selective for α(1a)- and α(1d)-adrenoceptors in radioligand binding studies (0.22 nM at α(1a)-, 0.97 nM at α(1d))- compared to α(1b)-sites (2.5 nM) and in isolated tissue bioassays (pA2 values of 8.9-9.0 for α(1A)-receptors in rat vas deferens or canine prostate strips, 9.1 at α(1D)-sites (rat aorta)), compared to 7.9 at α(1B)-sites (rat spleen). A-131701 also potently blocked radioligand binding to α1- adrenoceptors in canine and human prostatic membranes, but was considerably weaker at α2-adrenoceptors. In isoflurane-anesthetized dogs, A-131701 antagonized epinephrine-induced increases in intraurethral pressure (IUP) with a pseudo-pA2 value of 8.17. In spontaneously hypertensive rats. A- 131701 caused transient decreases in mean arterial blood pressure (MABP) and transient tachycardia. The area under curve (AUC0 →60 min for the hypotensive response was dose-related, with long index value A-131701 of 5.33, suggesting a selectivity of >600-fold comparing IUP to MABP effects. In pentobarbital-anesthetized dogs, A-131701 was more potent in blocking phenylephrine (PHE)-induced increases in IUP (pseudo-pA2 = 8.0), compared to concurrently measured MABP (pseudo-pA2 = 7.2), or sixfold selective. Doses greater than 1,000 nmol/kg i.v. of A-131701 were required to lower blood pressure by 10 mm Hg in these dogs (pED10 = 5.57), indicating a uroselectivity ratio of >250, superior to doxazosin, terazosin, or tamsulosin. Thus, A-131701 is selective for α(1A)- and α(1D)- vs. α(1B)- adrenoceptors in vitro, and prostatic function vs. blood pressure effects in vivo, which may provide therapeutic advantages in the treatment of BPH.

AB - New compounds selective for α(1A)-adrenoceptors in the prostate may offer enhanced efficacy for benign prostatic hyperplasia (BPH), with fewer side effects than current treatment. A-131701 (3-[2-((3aR,9bR)-cis-6-methoxy- 2,3,3a,4,5,9b,hexahydro-[1H]-benz[e]isoindol-2- yl)ethyl]pyridol]3',4':4,5]thieno [3,2-d]pyrimidine-2,4(1H,3H)-dione), from a novel class of benz[e]isolindole pyridothienopyrimidines and pyridothienopyrazines, is selective for α(1a)- and α(1d)-adrenoceptors in radioligand binding studies (0.22 nM at α(1a)-, 0.97 nM at α(1d))- compared to α(1b)-sites (2.5 nM) and in isolated tissue bioassays (pA2 values of 8.9-9.0 for α(1A)-receptors in rat vas deferens or canine prostate strips, 9.1 at α(1D)-sites (rat aorta)), compared to 7.9 at α(1B)-sites (rat spleen). A-131701 also potently blocked radioligand binding to α1- adrenoceptors in canine and human prostatic membranes, but was considerably weaker at α2-adrenoceptors. In isoflurane-anesthetized dogs, A-131701 antagonized epinephrine-induced increases in intraurethral pressure (IUP) with a pseudo-pA2 value of 8.17. In spontaneously hypertensive rats. A- 131701 caused transient decreases in mean arterial blood pressure (MABP) and transient tachycardia. The area under curve (AUC0 →60 min for the hypotensive response was dose-related, with long index value A-131701 of 5.33, suggesting a selectivity of >600-fold comparing IUP to MABP effects. In pentobarbital-anesthetized dogs, A-131701 was more potent in blocking phenylephrine (PHE)-induced increases in IUP (pseudo-pA2 = 8.0), compared to concurrently measured MABP (pseudo-pA2 = 7.2), or sixfold selective. Doses greater than 1,000 nmol/kg i.v. of A-131701 were required to lower blood pressure by 10 mm Hg in these dogs (pED10 = 5.57), indicating a uroselectivity ratio of >250, superior to doxazosin, terazosin, or tamsulosin. Thus, A-131701 is selective for α(1A)- and α(1D)- vs. α(1B)- adrenoceptors in vitro, and prostatic function vs. blood pressure effects in vivo, which may provide therapeutic advantages in the treatment of BPH.

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