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 A(2)/prostaglandin H(2) (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.
authors.affiliation: School of Pharmacy & Allied Health Professions, Creighton University, 2500 California Plaza, Omaha, NE 68005, USA.
authors.forename: Shankar L
authors.initials: SL
authors.lastname: Saha
authors.forename: Victoria F
authors.initials: VF
authors.lastname: Roche
authors.forename: Kathleen
authors.initials: K
authors.lastname: Pendola
authors.forename: Mark
authors.initials: M
authors.lastname: Kearley
authors.forename: Longping
authors.initials: L
authors.lastname: Lei
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Romstedt
authors.forename: Mark
authors.initials: M
authors.lastname: Herdman
authors.forename: Gamal
authors.initials: G
authors.lastname: Shams
authors.forename: Vivek
authors.initials: V
authors.lastname: Kaisare
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Feller
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011485:Protein Binding; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013329:Structure-Activity Relationship
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D007546:Isoquinolines; D010975:Platelet Aggregation Inhibitors; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2