Interaction of urapidil with brain serotonin-1A receptors increases the blood pressure reduction due to peripheral alpha-adrenoceptor inhibition

Sanders, Karl H.; Beller, Klaus-Dieter; Bischler, Paul; Kolassa, Norbert

doi:10.1097/00004872-198812001-00013

Cited by 6 publications

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“…[15][16][17][18][19][20] Compounds in cluster B (urapidil 13 and 5-methylurapidil 14 (CCS > 0.89)) are agonists at serotonin 5HT1A and antagonists at R 1 receptors. 25,[31][32][33][34] Compounds in cluster C (spiroxatrine 9 and WAY 100635 10 (CCS >0.826)) again have similar functional activity profiles: they are antagonists for R 1 and serotonin 5HT1A receptors. [23][24][25][26][27] Cluster D with the next highest similarity score (CCS > 0.82) contains dopamine 21, N-methyldopamine 22, and 6,7-ADTN 23.…”

Section: Relationship Between Biospectra Similarity and Functional Acmentioning

confidence: 99%

“…Accordingly, molecules residing in dendrogram section A of Figure (bromocriptine 4 , co-dergocrine 5 , and dihydroergocristine 6 (CCS > 0.91)) function as agonists at dopamine and α 2 -adrenergic receptors and as antagonists at the α 1 -adrenergic receptor. − Compounds in cluster B (urapidil 13 and 5-methylurapidil 14 (CCS > 0.89)) are agonists at serotonin 5HT1A and antagonists at α 1 receptors. ,− Compounds in cluster C (spiroxatrine 9 and WAY 100635 10 (CCS >0.826)) again have similar functional activity profiles: they are antagonists for α 1 and serotonin 5HT1A receptors. − Cluster D with the next highest similarity score (CCS > 0.82) contains dopamine 21, N -methyldopamine 22 , and 6,7-ADTN 23 . These three compounds are full agonists both at dopamine and at adrenergic receptors. ,− Ranking next in the hierarchical clustering are compounds in cluster E ( allyl norapomorphine 7 and norapomorphine 8 ( CCS > 0.80 )) , which are dopamine agonists. , …”

Section: Relationship Between Biospectra Similarity and Functional Ac...mentioning

confidence: 99%

“…25,[31][32][33][34] Compounds in cluster C (spiroxatrine 9 and WAY 100635 10 (CCS >0.826)) again have similar functional activity profiles: they are antagonists for R 1 and serotonin 5HT1A receptors. [23][24][25][26][27] Cluster D with the next highest similarity score (CCS > 0.82) contains dopamine 21, N-methyldopamine 22, and 6,7-ADTN 23. These three compounds are full agonists both at dopamine and at adrenergic receptors.…”

Section: Relationship Between Biospectra Similarity and Functional Ac...mentioning

confidence: 99%

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Biospectra Analysis: Model Proteome Characterizations for Linking Molecular Structure and Biological Response

et al. 2005

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Establishing quantitative relationships between molecular structure and broad biological effects has been a long-standing goal in drug discovery. Evaluation of the capacity of molecules to modulate protein functions is a prerequisite for understanding the relationship between molecular structure and in vivo biological response. A particular challenge in these investigations is to derive quantitative measurements of a molecule's functional activity pattern across different proteins. Herein we describe an operationally simple probabilistic structure-activity relationship (SAR) approach, termed biospectra analysis, for identifying agonist and antagonist effect profiles of medicinal agents by using pattern similarity between biological activity spectra (biospectra) of molecules as the determinant. Accordingly, in vitro binding data (percent inhibition values of molecules determined at single high drug concentration in a battery of assays representing a cross section of the proteome) are useful for identifying functional effect profile similarity between medicinal agents. To illustrate this finding, the relationship between biospectra similarity of 24 molecules, identified by hierarchical clustering of a 1567 molecule dataset as being most closely aligned with the neurotransmitter dopamine, and their agonist or antagonist properties was probed. Distinguishing the results described in this study from those obtained with affinity-based methods, the observed association between biospectra and biological response profile similarity remains intact even upon removal of putative drug targets from the dataset (four dopaminergic [D 1 /D 2 /D 3 /D 4 ] and two adrenergic [R 1 and R 2 ] receptors). These findings indicate that biospectra analysis provides an unbiased new tool for forecasting structure-response relationships and for translating broad biological effect information into chemical structure design.

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Section: Relationship Between Biospectra Similarity and Functional Acmentioning

confidence: 99%

Section: Relationship Between Biospectra Similarity and Functional Ac...mentioning

confidence: 99%

Section: Relationship Between Biospectra Similarity and Functional Ac...mentioning

confidence: 99%

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Biospectra Analysis: Model Proteome Characterizations for Linking Molecular Structure and Biological Response

et al. 2005

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“…Doods et al (1988) were unable to prevent the central hypotensive action caused by urapidil using (-)-pindolol, which is known to block 5-HTlA receptors (Schoeffter & Hoyer, 1988;Hoyer, 1988). On the other hand, spiroxatrine, another putative 5-HT1A receptor antagonist (Nelson & Taylor, 1986) was found to attenuate the hypotensive effect of urapidil (Sanders et al, 1988;Kolassa et al, 1989). However, spiroxatrine alone caused a fall in blood pressure which may have contributed to the apparent antagonism of the hypotension caused by urapidil, while in the experiments of Doods et al (1988) it is possible that the al-adrenoceptor antagonist action of urapidil was masking the ability of (-)-pindolol to attenuate the hypotensive action of urapidil.…”

Section: Introductionmentioning

confidence: 98%

The mechanism of the sympathoinhibitory action of urapidil: role of 5‐HT_1A receptors

Ramage

1991

British J Pharmacology

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1 An investigation was carried out to determine if the sympathoinhibition caused by urapidil is due to activation of 5-HTlA receptors by investigating whether it could be reversed by the non-selective 5-HTIA receptor antagonist spiperone. To control for the possibility of functional antagonism by spiperone, the ability of spiperone to reverse the sympathoinhibition caused by clonidine was also investigated. These experiments were carried out in anaesthetized prazosin-pretreated cats to prevent the a,-adrenoceptor antagonist action of urapidil and spiperone from masking any effects observed.2 Cats were anaesthetized with ac-chloralose and simultaneous recordings were made of whole cardiac, splanchnic and renal nerve activities, blood pressure, heart ;ate and femoral arterial flow (from which conductance was derived). All animals were initially pretreated with prazosin (1 mgkg -1, i.v.) given in divided doses (0.75 followed 10min later by 0.25mgkg-1), then either urapidil (0.75mgkg-1, i.v.) or clonidine (10,ug kg-1, i.v. in two divided doses) followed by 3 separate injections of spiperone (1 mg kg 1, i.v.). In another set of experiments urapidil was given followed by injections of the appropriate vehicle for spiperone, while in another set urapidil was replaced with an injection of the appropriate vehicle followed by injections of spiperone. In the experiments with clonidine, the a2-adrenoceptor antagonist Wy 26392 (0.3 mg kg-1) was given after the last injection of spiperone.3 The prazosin pretreatment caused a fall in blood pressure associated with femoral vasodilatation, a small bradycardia and little change in cardiac, splanchnic or renal nerve activities. Urapidil or clonidine injection after prazosin caused sympathoinhibition associated with an additional bradycardia. However, only urapidil caused an additional fall in blood pressure. Spiperone injections reversed the sympathoinhibition caused by urapidil but not that caused by clonidine. The sympathoinhibition caused by clonidine was reversed by the a2-adrenoceptor antagonist Wy 26392. 4 These results show that the sympathoinhibition caused by urapidil in prazosin-pretreated cats can be reversed by spiperone. The reversal of this sympathoinhibition is not due to functional antagonism. It is concluded that urapidil can cause sympathoinhibition by activation of 5-HTlA receptors.

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U

Albinus

Amschler

et al. 1994

Hagers Handbuch Der Pharmazeutischen Praxis

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Interaction of urapidil with brain serotonin-1A receptors increases the blood pressure reduction due to peripheral alpha-adrenoceptor inhibition

Cited by 6 publications

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Biospectra Analysis: Model Proteome Characterizations for Linking Molecular Structure and Biological Response

Biospectra Analysis: Model Proteome Characterizations for Linking Molecular Structure and Biological Response

The mechanism of the sympathoinhibitory action of urapidil: role of 5‐HT_1A receptors

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Interaction of urapidil with brain serotonin-1A receptors increases the blood pressure reduction due to peripheral alpha-adrenoceptor inhibition

Cited by 6 publications

References 0 publications

Biospectra Analysis: Model Proteome Characterizations for Linking Molecular Structure and Biological Response

Biospectra Analysis: Model Proteome Characterizations for Linking Molecular Structure and Biological Response

The mechanism of the sympathoinhibitory action of urapidil: role of 5‐HT1A receptors

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The mechanism of the sympathoinhibitory action of urapidil: role of 5‐HT_1A receptors