Synthesis and in vitro platelet aggregation and TP receptor binding studies on bicyclic 5,8-ethanooctahydroisoquinolines and 5,8-ethanotetrahydroisoquinolines

Shankar L. Saha; Victoria F. Roche; Kathleen Pendola; Mark Kearley; Longping Lei; Karl J. Romstedt; Mark Herdman; Gamal Shams; Vivek Kaisare; Dennis R. Feller

doi:10.1016/S0968-0896(02)00101-3

Synthesis and in vitro platelet aggregation and TP receptor binding studies on bicyclic 5,8-ethanooctahydroisoquinolines and 5,8-ethanotetrahydroisoquinolines

Shankar L. Saha, Victoria F. Roche, Kathleen Pendola, Mark Kearley, Longping Lei, Karl J. Romstedt, Mark Herdman, Gamal Shams, Vivek Kaisare, Dennis R. Feller

Department of Pharmacy Sciences

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Eighteen novel bicyclic 1-substituted benzyl octahydro- and tetrahydroisoquinolines were synthesized and evaluated for human thromboxane A₂/prostaglandin H₂ (TP) receptor affinity and antagonism of TP receptor-mediated platelet aggregation. In both cases, potency depended more on the presence of methoxy groups on the 1-benzyl moiety than on nitrogen substitution or extent of oxidation of the isoquinoline ring system. The most potent of the bicyclic compounds retained the 5,8-ethanooctahydroisoquinoline ring structure of the parent molecule (1) and required the 3,4,5-trimethoxybenzyl substitution pattern found in the well-characterized tetrahydroisoquinoline antiplatelet agent trimetoquinol. Differences in nitrogen substituent SAR were noted between the mono-methoxylated compounds and the 3,4,5-trimethoxybenzyl derivatives.

Original language	English (US)
Pages (from-to)	2779-2793
Number of pages	15
Journal	Bioorganic and Medicinal Chemistry
Volume	10
Issue number	8
DOIs	https://doi.org/10.1016/S0968-0896(02)00101-3
State	Published - 2002

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/S0968-0896(02)00101-3

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Saha, S. L., Roche, V. F., Pendola, K., Kearley, M., Lei, L., Romstedt, K. J., Herdman, M., Shams, G., Kaisare, V., & Feller, D. R. (2002). Synthesis and in vitro platelet aggregation and TP receptor binding studies on bicyclic 5,8-ethanooctahydroisoquinolines and 5,8-ethanotetrahydroisoquinolines. Bioorganic and Medicinal Chemistry, 10(8), 2779-2793. https://doi.org/10.1016/S0968-0896(02)00101-3

Synthesis and in vitro platelet aggregation and TP receptor binding studies on bicyclic 5,8-ethanooctahydroisoquinolines and 5,8-ethanotetrahydroisoquinolines. / Saha, Shankar L.; Roche, Victoria F.; Pendola, Kathleen; Kearley, Mark; Lei, Longping; Romstedt, Karl J.; Herdman, Mark; Shams, Gamal; Kaisare, Vivek; Feller, Dennis R.

In: Bioorganic and Medicinal Chemistry, Vol. 10, No. 8, 2002, p. 2779-2793.

Research output: Contribution to journal › Article › peer-review

Saha, SL, Roche, VF, Pendola, K, Kearley, M, Lei, L, Romstedt, KJ, Herdman, M, Shams, G, Kaisare, V & Feller, DR 2002, 'Synthesis and in vitro platelet aggregation and TP receptor binding studies on bicyclic 5,8-ethanooctahydroisoquinolines and 5,8-ethanotetrahydroisoquinolines', Bioorganic and Medicinal Chemistry, vol. 10, no. 8, pp. 2779-2793. https://doi.org/10.1016/S0968-0896(02)00101-3

Saha, Shankar L. ; Roche, Victoria F. ; Pendola, Kathleen ; Kearley, Mark ; Lei, Longping ; Romstedt, Karl J. ; Herdman, Mark ; Shams, Gamal ; Kaisare, Vivek ; Feller, Dennis R. / Synthesis and in vitro platelet aggregation and TP receptor binding studies on bicyclic 5,8-ethanooctahydroisoquinolines and 5,8-ethanotetrahydroisoquinolines. In: Bioorganic and Medicinal Chemistry. 2002 ; Vol. 10, No. 8. pp. 2779-2793.

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title = "Synthesis and in vitro platelet aggregation and TP receptor binding studies on bicyclic 5,8-ethanooctahydroisoquinolines and 5,8-ethanotetrahydroisoquinolines",

abstract = "Eighteen novel bicyclic 1-substituted benzyl octahydro- and tetrahydroisoquinolines were synthesized and evaluated for human thromboxane A2/prostaglandin H2 (TP) receptor affinity and antagonism of TP receptor-mediated platelet aggregation. In both cases, potency depended more on the presence of methoxy groups on the 1-benzyl moiety than on nitrogen substitution or extent of oxidation of the isoquinoline ring system. The most potent of the bicyclic compounds retained the 5,8-ethanooctahydroisoquinoline ring structure of the parent molecule (1) and required the 3,4,5-trimethoxybenzyl substitution pattern found in the well-characterized tetrahydroisoquinoline antiplatelet agent trimetoquinol. Differences in nitrogen substituent SAR were noted between the mono-methoxylated compounds and the 3,4,5-trimethoxybenzyl derivatives.",

author = "Saha, {Shankar L.} and Roche, {Victoria F.} and Kathleen Pendola and Mark Kearley and Longping Lei and Romstedt, {Karl J.} and Mark Herdman and Gamal Shams and Vivek Kaisare and Feller, {Dennis R.}",

note = "Funding Information: The authors gratefully acknowledge financial support for this project from the Nebraska Department of Health. The Nebraska Center for Mass Spectrometry, which performed the high resolution analysis of selected bicyclic molecules, is also acknowledged.",

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doi = "10.1016/S0968-0896(02)00101-3",

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AU - Roche, Victoria F.

AU - Pendola, Kathleen

AU - Kearley, Mark

AU - Lei, Longping

AU - Romstedt, Karl J.

AU - Herdman, Mark

AU - Shams, Gamal

AU - Kaisare, Vivek

AU - Feller, Dennis R.

N1 - Funding Information: The authors gratefully acknowledge financial support for this project from the Nebraska Department of Health. The Nebraska Center for Mass Spectrometry, which performed the high resolution analysis of selected bicyclic molecules, is also acknowledged.

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Synthesis and in vitro platelet aggregation and TP receptor binding studies on bicyclic 5,8-ethanooctahydroisoquinolines and 5,8-ethanotetrahydroisoquinolines

Abstract

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