Structure-activity studies of new imidazolines on adrenoceptors of rat aorta and human platelets

B. V. Venkataraman, G. Shams, A. Hamada, Y. Amemiya, V. Tantishaiyakul, F. Hsu, J. Fashempour, K. J. Romstedt, Duane Miller, D. R. Feller, P. N. Patil

Research output: Contribution to journalArticle

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Abstract

Potencies of new aromatic substituted fluoro or iodo analogues of catecholimidazolines on functional responses in rat aorta (α1) and platelets (α2) were quantified. (1) When compared either on the basis of EC50 or the dissociation constant (KA), 5-fluorocatecholimidazoline was as potent as the reference α1-adrenoceptor agonist, phenylephrine in the vascular tissue. The maximum contraction of aorta produced by the fluoro analogue was, however, 17% higher than that of phenylephrine. The time required for 1/2 relaxation of the tissue after 5-fluoro hydroxy imidazoline was at least twice as long as that of the phenylephrine. The catechol moiety as well as fluorine substitution at the critical 5-position of the aromatic ring is essential for higher α1 adrenoceptor-mediated potency. (2) As compared to the fluoro analogues, the adrenoceptor-mediated potencies of iodo-analogues were relatively weak on vascular tissue. Naphazoline and its analogues were partial agonists on vascular tissue with dissociation constants which ranged from 110 to 2600 nmol/l. (3) Imida zole analogues were generally less potent agonist than the imida zolines by one order of magnitude. (4) The vascular effects of all agonists were competitively blocked by prazosin with KB values which ranged from 0.04 to 0.48 nmol/l. Since the variation in KB values were within normal limits, the action of new imidazolines on rat aorta appears to be mediated mainly by the activation of the α1-adrenoceptor. Prazosin 10 nmol/l abolished the vascular response of some partial agonists. This indicates a slightly different mode of interaction of agonists with the transduction process. (5) Carbon 4-substituted imidazolines produced little or no α1 adrenoceptor-mediated intrinsic activity, but competitive receptor blocking potency was comparable to that of phentolamine. (6) Medetomidine was a partial agonist on the rat aorta with a KA of 260 nmol/l. When investigated as a blocker, the KB of medetomidine against phenylephrine was approximately 5600 nmol/l. The variation in the latter value was high. (7) In acetylsalicylic acid-treated human platelets, the α2-adrenoceptor-mediated aggregatory effect of all fluoro analogues was weak. lodo or naphazoline analogues did not initiate platelet aggregation but blocked the aggregation induced by epinephrine. The affinity of naphazoline for the α2-adrenoceptor was 1100 nmol/l. The IC50 of medetomidine for platelet anti-aggregatory effect was 3300 nmol/l, which compares favorably with other imidazoline type of blockes of platelet aggregation. (8) Sympathomimetic vasoconstrictor actions and platelet aggregation effects of these compounds can be dissociated. Some vasoconstrictors were antiaggregatory. The structure-activity relationships of the two receptor systems, namely rat aorta (α1) and platelets (α2), are discussed.

Original languageEnglish (US)
Pages (from-to)454-463
Number of pages10
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume344
Issue number4
DOIs
StatePublished - Oct 1 1991
Externally publishedYes

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Imidazolines
Adrenergic Receptors
Aorta
Blood Platelets
Medetomidine
Blood Vessels
Phenylephrine
Naphazoline
Platelet Aggregation
Prazosin
Vasoconstrictor Agents
Sympathomimetics
Fluorine
Phentolamine
Structure-Activity Relationship
Epinephrine
Aspirin
Inhibitory Concentration 50
Carbon

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Venkataraman, B. V., Shams, G., Hamada, A., Amemiya, Y., Tantishaiyakul, V., Hsu, F., ... Patil, P. N. (1991). Structure-activity studies of new imidazolines on adrenoceptors of rat aorta and human platelets. Naunyn-Schmiedeberg's Archives of Pharmacology, 344(4), 454-463. https://doi.org/10.1007/BF00172586

Structure-activity studies of new imidazolines on adrenoceptors of rat aorta and human platelets. / Venkataraman, B. V.; Shams, G.; Hamada, A.; Amemiya, Y.; Tantishaiyakul, V.; Hsu, F.; Fashempour, J.; Romstedt, K. J.; Miller, Duane; Feller, D. R.; Patil, P. N.

In: Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 344, No. 4, 01.10.1991, p. 454-463.

Research output: Contribution to journalArticle

Venkataraman, BV, Shams, G, Hamada, A, Amemiya, Y, Tantishaiyakul, V, Hsu, F, Fashempour, J, Romstedt, KJ, Miller, D, Feller, DR & Patil, PN 1991, 'Structure-activity studies of new imidazolines on adrenoceptors of rat aorta and human platelets', Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 344, no. 4, pp. 454-463. https://doi.org/10.1007/BF00172586
Venkataraman, B. V. ; Shams, G. ; Hamada, A. ; Amemiya, Y. ; Tantishaiyakul, V. ; Hsu, F. ; Fashempour, J. ; Romstedt, K. J. ; Miller, Duane ; Feller, D. R. ; Patil, P. N. / Structure-activity studies of new imidazolines on adrenoceptors of rat aorta and human platelets. In: Naunyn-Schmiedeberg's Archives of Pharmacology. 1991 ; Vol. 344, No. 4. pp. 454-463.
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T1 - Structure-activity studies of new imidazolines on adrenoceptors of rat aorta and human platelets

AU - Venkataraman, B. V.

AU - Shams, G.

AU - Hamada, A.

AU - Amemiya, Y.

AU - Tantishaiyakul, V.

AU - Hsu, F.

AU - Fashempour, J.

AU - Romstedt, K. J.

AU - Miller, Duane

AU - Feller, D. R.

AU - Patil, P. N.

PY - 1991/10/1

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N2 - Potencies of new aromatic substituted fluoro or iodo analogues of catecholimidazolines on functional responses in rat aorta (α1) and platelets (α2) were quantified. (1) When compared either on the basis of EC50 or the dissociation constant (KA), 5-fluorocatecholimidazoline was as potent as the reference α1-adrenoceptor agonist, phenylephrine in the vascular tissue. The maximum contraction of aorta produced by the fluoro analogue was, however, 17% higher than that of phenylephrine. The time required for 1/2 relaxation of the tissue after 5-fluoro hydroxy imidazoline was at least twice as long as that of the phenylephrine. The catechol moiety as well as fluorine substitution at the critical 5-position of the aromatic ring is essential for higher α1 adrenoceptor-mediated potency. (2) As compared to the fluoro analogues, the adrenoceptor-mediated potencies of iodo-analogues were relatively weak on vascular tissue. Naphazoline and its analogues were partial agonists on vascular tissue with dissociation constants which ranged from 110 to 2600 nmol/l. (3) Imida zole analogues were generally less potent agonist than the imida zolines by one order of magnitude. (4) The vascular effects of all agonists were competitively blocked by prazosin with KB values which ranged from 0.04 to 0.48 nmol/l. Since the variation in KB values were within normal limits, the action of new imidazolines on rat aorta appears to be mediated mainly by the activation of the α1-adrenoceptor. Prazosin 10 nmol/l abolished the vascular response of some partial agonists. This indicates a slightly different mode of interaction of agonists with the transduction process. (5) Carbon 4-substituted imidazolines produced little or no α1 adrenoceptor-mediated intrinsic activity, but competitive receptor blocking potency was comparable to that of phentolamine. (6) Medetomidine was a partial agonist on the rat aorta with a KA of 260 nmol/l. When investigated as a blocker, the KB of medetomidine against phenylephrine was approximately 5600 nmol/l. The variation in the latter value was high. (7) In acetylsalicylic acid-treated human platelets, the α2-adrenoceptor-mediated aggregatory effect of all fluoro analogues was weak. lodo or naphazoline analogues did not initiate platelet aggregation but blocked the aggregation induced by epinephrine. The affinity of naphazoline for the α2-adrenoceptor was 1100 nmol/l. The IC50 of medetomidine for platelet anti-aggregatory effect was 3300 nmol/l, which compares favorably with other imidazoline type of blockes of platelet aggregation. (8) Sympathomimetic vasoconstrictor actions and platelet aggregation effects of these compounds can be dissociated. Some vasoconstrictors were antiaggregatory. The structure-activity relationships of the two receptor systems, namely rat aorta (α1) and platelets (α2), are discussed.

AB - Potencies of new aromatic substituted fluoro or iodo analogues of catecholimidazolines on functional responses in rat aorta (α1) and platelets (α2) were quantified. (1) When compared either on the basis of EC50 or the dissociation constant (KA), 5-fluorocatecholimidazoline was as potent as the reference α1-adrenoceptor agonist, phenylephrine in the vascular tissue. The maximum contraction of aorta produced by the fluoro analogue was, however, 17% higher than that of phenylephrine. The time required for 1/2 relaxation of the tissue after 5-fluoro hydroxy imidazoline was at least twice as long as that of the phenylephrine. The catechol moiety as well as fluorine substitution at the critical 5-position of the aromatic ring is essential for higher α1 adrenoceptor-mediated potency. (2) As compared to the fluoro analogues, the adrenoceptor-mediated potencies of iodo-analogues were relatively weak on vascular tissue. Naphazoline and its analogues were partial agonists on vascular tissue with dissociation constants which ranged from 110 to 2600 nmol/l. (3) Imida zole analogues were generally less potent agonist than the imida zolines by one order of magnitude. (4) The vascular effects of all agonists were competitively blocked by prazosin with KB values which ranged from 0.04 to 0.48 nmol/l. Since the variation in KB values were within normal limits, the action of new imidazolines on rat aorta appears to be mediated mainly by the activation of the α1-adrenoceptor. Prazosin 10 nmol/l abolished the vascular response of some partial agonists. This indicates a slightly different mode of interaction of agonists with the transduction process. (5) Carbon 4-substituted imidazolines produced little or no α1 adrenoceptor-mediated intrinsic activity, but competitive receptor blocking potency was comparable to that of phentolamine. (6) Medetomidine was a partial agonist on the rat aorta with a KA of 260 nmol/l. When investigated as a blocker, the KB of medetomidine against phenylephrine was approximately 5600 nmol/l. The variation in the latter value was high. (7) In acetylsalicylic acid-treated human platelets, the α2-adrenoceptor-mediated aggregatory effect of all fluoro analogues was weak. lodo or naphazoline analogues did not initiate platelet aggregation but blocked the aggregation induced by epinephrine. The affinity of naphazoline for the α2-adrenoceptor was 1100 nmol/l. The IC50 of medetomidine for platelet anti-aggregatory effect was 3300 nmol/l, which compares favorably with other imidazoline type of blockes of platelet aggregation. (8) Sympathomimetic vasoconstrictor actions and platelet aggregation effects of these compounds can be dissociated. Some vasoconstrictors were antiaggregatory. The structure-activity relationships of the two receptor systems, namely rat aorta (α1) and platelets (α2), are discussed.

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