Synthesis and Investigation of the Adrenoceptor Agonist and Platelet Antiaggregatory Properties of 1,7,8-Trisubstituted Analogues of Trimetoquinol

Michael T. Clark, Jane Chang, Stephen S. Navran, H. A. Huzoor-Akbar, Asoke MUKhopadhyay, Hebatalla Amin, Dennis R. Feller, Duane Miller

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The synthesis and biological evaluation of 7,8-dihydroxy (2) and 7,8-methylenedioxy (3) analogues of on 0-adrenoceptor systems and human platelets were undertaken and compared with trimetoquinol (TMQ, 1). Whereas 1 is a agonist in Guinea pig atria and trachea (pD2 = 8.2), analogue 2 was marginally effective at relaxing Guinea pig tracheal smooth muscle (pD2 = 4.4) and inactive as an agonist on Guinea pig atria. Analogues 2 and 3 were inhibitors of phospholipase C (PLC; from Clostridium perfringens) induced and secondary wave of ADP-induced aggregation responses and inactive against low-dose thrombin-induced or stable endoperoxide (U46619) induced human platelet aggregation. Against ADP-induced serotonin secretion, 3 was 9-fold more active than analogue 2. Further, the rank order of TMQ isomers and 3 as inhibitors of PLC-induced platelet aggregation, serotonin secretion, and phosphatidylinositol degradation was identical. The results suggest that these compounds are blocking the action of PLC by interfering with phosphatidylinositol turnover in platelet membranes. The inhibition of ADP-induced responses in human platelets by analogues 2 and 3 also suggests a site of inhibition at a level of arachidonic acid release. Thus, ring expansion of 1 as in the benzazepine analogues 2 and 3 has allowed us to develop selective inhibitors of platelet function that lack significant 0-adrenoceptor activity.

Original languageEnglish (US)
Pages (from-to)181-185
Number of pages5
JournalJournal of Medicinal Chemistry
Volume29
Issue number2
DOIs
StatePublished - Jan 1 1986
Externally publishedYes

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Tretoquinol
Adenosine Diphosphate
Adrenergic Receptors
Guinea Pigs
Blood Platelets
Phosphatidylinositols
Platelet Aggregation
Serotonin
Benzazepines
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Clostridium perfringens
Platelet Aggregation Inhibitors
Type C Phospholipases
Trachea
Arachidonic Acid
Thrombin
Smooth Muscle
Membranes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and Investigation of the Adrenoceptor Agonist and Platelet Antiaggregatory Properties of 1,7,8-Trisubstituted Analogues of Trimetoquinol. / Clark, Michael T.; Chang, Jane; Navran, Stephen S.; Huzoor-Akbar, H. A.; MUKhopadhyay, Asoke; Amin, Hebatalla; Feller, Dennis R.; Miller, Duane.

In: Journal of Medicinal Chemistry, Vol. 29, No. 2, 01.01.1986, p. 181-185.

Research output: Contribution to journalArticle

Clark, Michael T. ; Chang, Jane ; Navran, Stephen S. ; Huzoor-Akbar, H. A. ; MUKhopadhyay, Asoke ; Amin, Hebatalla ; Feller, Dennis R. ; Miller, Duane. / Synthesis and Investigation of the Adrenoceptor Agonist and Platelet Antiaggregatory Properties of 1,7,8-Trisubstituted Analogues of Trimetoquinol. In: Journal of Medicinal Chemistry. 1986 ; Vol. 29, No. 2. pp. 181-185.
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