Further characterization of the 5-hydroxytryptamine 5-HT1-like receptor mediating contraction of guinea-pig iliac artery

Schoeffter, Philippe; Şahin-Erdemli, İnci

doi:10.1016/0014-2999(92)90309-r

Cited by 10 publications

(5 citation statements)

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“…The¯at concentration±effect curve and the low pA 2 value of 7Á8 for the antagonism by methiothepin (0Á1 mM) of the contractile response of 3 makes it doubtful that the compound interacted with a single type of 5-HT receptor. Similar observations with methysergide and metergoline in guinea-pig iliac artery moderately precontracted by PGF 2a were made by Schoeffter & Sahin-Erdemli (1992). On the other hand, these authors demonstrated in the same study that partial agonists could be used as antagonists since they failed to contract the artery when added before the PGF 2a -induced precontraction.…”

Section: Discussionsupporting

confidence: 73%

Simple O-Acylated Derivatives of Lysergol and Dihydrolysergol-I: Synthesis and Interaction with 5-HT2A, 5-HT2C and 5-HT1B Receptors, and α1 Adrenergic Receptors

Pertz

Brown

Gager

et al. 1999

Journal of Pharmacy and Pharmacology

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A series of simple O-acylated derivatives of the naturally occurring clavine alkaloids lysergol and dihydrolysergol-I were synthesized and tested in-vitro for their ability to interact with 5-HT2A receptors in rat tail artery, 5-HT2C receptors in piglet choroid plexus, 5-HT1B receptors in guinea-pig iliac artery and alpha1-adrenergic receptors in rat aorta. In contrast to the classical ergoline 5-HT2A receptor antagonists methysergide and LY53857, the compounds produced competitive antagonism of the 5-HT response in rat tail artery. Affinities of ergolines 3-14 were higher (pA2 values of 7.33-8.40) than those of the parent alcohols lysergol (1) and dihydrolysergol-I (2), respectively. The introduction of an isopropyl substituent at the N(1) position of the compounds failed to enhance 5-HT2A receptor affinity. Compounds 3-14 exhibited lower affinities for alpha1-adrenergic receptors than for 5-HT2A receptors. In particular, those lysergol derivatives that had an isopropyl substituent at the N(1) position were highly specific 5-HT2A receptor antagonists (ratio 5-HT2A/alpha1 = 302-3548). Selected derivatives of lysergol (3-5, 9-11) which were assayed for radioligand binding at 5-HT2C receptors in piglet choroid plexus had affinities that were similar to those found in rat tail artery. Additionally, lysergol and its N(1)-unsubstituted derivatives were found to be partial agonists (alpha of 0.2-0.4) for 5-HT2C receptor-mediated inositol phosphate accumulation in piglet choroid plexus. On the other hand, analogues with an isopropyl substituent at N(1) showed no measurable agonist activity. The observation that N(1)-unsubstituted derivatives of lysergol possessed agonist properties at 5-HT2C receptors whereas their agonist activity at 5-HT2A receptors was marginal (alpha of 0.05 for compound 3 at 1 microM) or not measurable, suggests that these compounds have different abilities to cause conformational change at the two receptor types. Selected derivatives of lysergol (3-5, 9-11) which were examined as ligands for 5-HT1B receptors in guinea-pig iliac artery caused insurmountable blockade of the contractile effect of 5-HT. N(1)-isopropyl derivatives had 30-50-fold lower affinities for 5-HT1B receptors of this tissue than their N(1)-unsubstituted analogues. It is concluded that O-acylated derivatives of the clavine alkaloids lysergol and dihydrolysergol-I mimic therapeutically relevant ergolines due to the complexity of their pharmacological profile as partial agonists and antagonists at 5-HT2A, 5-HT2C and 5-HT1B receptors, and at alpha1-adrenergic receptors.

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Section: Discussionsupporting

confidence: 73%

Simple O-Acylated Derivatives of Lysergol and Dihydrolysergol-I: Synthesis and Interaction with 5-HT2A, 5-HT2C and 5-HT1B Receptors, and α1 Adrenergic Receptors

Pertz

Brown

Gager

et al. 1999

Journal of Pharmacy and Pharmacology

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“…Analysis of agonist and antagonist characteristics indicates that the receptor present in the pre-contracted rabbit mesenteric artery is very similar to other 5-HT receptors mediating vasoconstriction. Notably, those in guinea-pig iliac artery (Schoeffter & Sahin-Erdemli, 1992), rabbit renal artery (Choppin & O'Connor, 1994) and human pial artery (Hamel & Bouchard, 1991) which have been variously classified as 5-HTI-like, 5-HTlD-like or 5-HTlD in nature. We have already underlined the similarity of the receptor found in the rabbit mesenteric artery to the 5-HTID binding site, however, the relatively modest antagonist potency of metergoline in our study appears somewhat inconsistent with a 5-HTlD classification.…”

Section: Resultsmentioning

confidence: 99%

Presence of vasoconstrictor 5HT₁‐like receptors revealed by precontraction of rabbit isolated mesenteric artery

Choppin¹,

O'Connor²

1995

British J Pharmacology

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1 A series of 5-hydroxytryptamine (5-HT) receptor agonists including 5-HT, 5-carboxamidotryptamine (5-CT) and sumatriptan produced little or no contraction of rabbit isolated mesenteric arteries under resting tone conditions, even at concentrations up to 10-4 M. 2 When the same agonists were retested in mesenteric artery preparations pre-contracted with the thromboxane-mimetic, U46619, each demonstrated concentration-related vasoconstrictor activity. 5-CT and 5-HT were especially potent and effective in this model giving EC50 values of 4.3 x 10-9 M and 1.6 x 10-8 M respectively and maximum effects equivalent to those of KCI 80 mM. In preparations precontracted by U46619 (conditions retained throughout the rest of the study) the order of agonist potency was 5-CT > 5-HT > RU 24969 = sumatriptan > 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) > cisapride. 3 The vasoconstrictor effects of 5-CT were competitively antagonized by methiothepin (pA2 8.20) receptors do not make a significant contribution in this model. 6 Hence, precontraction of rabbit mesenteric arteries reveals potent vasoconstrictor effects of 5-HT and related agonists. Based on the agonist potency order and the antagonist studies performed, the receptor subtype responsible has the characteristics of a 5-HTI-like receptor. This study therefore demonstrates a particularly striking example of vasoconstrictor synergy involving 5-HTI-like receptors.

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“…(PGF2J. A preliminary account of this work was presented at the 1990 Spring Meeting of the German Pharmacological Society (Schoeffter & Sahin-Erdemli, 1990).…”

Section: Introductionmentioning

confidence: 99%

5‐HT₁‐like receptors mediate 5‐hydroxytryptamine‐induced contraction of guinea‐pig isolated iliac artery

Şahin-Erdemli

Hoyer

Stoll

et al. 1991

British J Pharmacology

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1 The effects of 5-hydroxytryptamine (5-HT) and of the 5-HT1-like receptor agonists, 5-carboxamidotryptamine (5-CT) and sumatriptan (GR43175) were investigated in isolated ring preparations of guinea-pig common iliac artery. 2 The three agonists induced very weak, if any, contractions of unstimulated preparations, whereas they elicited concentration-dependent contractions in preparations given a moderate tone by a threshold concentration of prostaglandin F2& (PGF2.). 3 Under the latter conditions, Emax values for 5-HT and 5-CT reached about 45% of PGF2. maximal effect, whereas the Emax value of sumatriptan was significantly lower (about 35%). The rank order of potency (mean EC50 value, nM) was 5-CT (6.6) > 5-HT (22.9) > sumatriptan (155). Pargyline, cocaine or deoxycorticosterone were without significant effect on the contractions induced by 5-HT. 4 The 5-HT3 receptor antagonist, (laH,3a,5aH-tropan-3-yl) 1-H-indole-3-carboxylic acid ester ; 1 gM), had no effect on 5-HT-, 5-CT-and sumatriptan-induced contractions. 5The 5-HT2 receptor antagonist, ketanserin (1/AM) caused only small rightward shifts (concentrationratios, about 2) in the concentration-response curves to 5-HT, 5-CT and sumatriptan without significantly depressing the maximum effects. 6 In the presence of ketanserin (1 1M), the non-selective 5-HT receptor antagonist, methiothepin (0.1 pM), shifted the concentration-response curves to 5-HT and 5-CT to the right in a parallel manner and to a similar extent for both agonists (respective mean pKB values, 8.07 and 8.27). The effect of sumatriptan was also antagonized by methiothepin, but solvent effects precluded quantitative analysis of this antagonism. 7 It is concluded that 5-HT1-like receptors mediate the contractions induced by 5-HT, 5-CT and sumatriptan in guinea-pig isolated iliac artery. For reasons not yet understood, these receptors are detected only when the tissues are moderately pre-contracted by PGF2x.

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Further characterization of the 5-hydroxytryptamine 5-HT1-like receptor mediating contraction of guinea-pig iliac artery

Cited by 10 publications

References 28 publications

Simple O-Acylated Derivatives of Lysergol and Dihydrolysergol-I: Synthesis and Interaction with 5-HT2A, 5-HT2C and 5-HT1B Receptors, and α1 Adrenergic Receptors

Simple O-Acylated Derivatives of Lysergol and Dihydrolysergol-I: Synthesis and Interaction with 5-HT2A, 5-HT2C and 5-HT1B Receptors, and α1 Adrenergic Receptors

Presence of vasoconstrictor 5HT₁‐like receptors revealed by precontraction of rabbit isolated mesenteric artery

5‐HT₁‐like receptors mediate 5‐hydroxytryptamine‐induced contraction of guinea‐pig isolated iliac artery

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Further characterization of the 5-hydroxytryptamine 5-HT1-like receptor mediating contraction of guinea-pig iliac artery

Cited by 10 publications

References 28 publications

Simple O-Acylated Derivatives of Lysergol and Dihydrolysergol-I: Synthesis and Interaction with 5-HT2A, 5-HT2C and 5-HT1B Receptors, and α1 Adrenergic Receptors

Simple O-Acylated Derivatives of Lysergol and Dihydrolysergol-I: Synthesis and Interaction with 5-HT2A, 5-HT2C and 5-HT1B Receptors, and α1 Adrenergic Receptors

Presence of vasoconstrictor 5HT1‐like receptors revealed by precontraction of rabbit isolated mesenteric artery

5‐HT1‐like receptors mediate 5‐hydroxytryptamine‐induced contraction of guinea‐pig isolated iliac artery

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Presence of vasoconstrictor 5HT₁‐like receptors revealed by precontraction of rabbit isolated mesenteric artery

5‐HT₁‐like receptors mediate 5‐hydroxytryptamine‐induced contraction of guinea‐pig isolated iliac artery