title: Structure-affinity relationships of arylquinolizines at alpha-adrenoceptors.
abstract: Hexahydroaryl[a]quinolizines comprise a prominent structural element in several alpha 2-adrenoceptor antagonists. Eight hexahydroheteroarylquinolizines were prepared as minimal ligands to investigate the relationship between the nature of the aromatic ring and affinity of these molecules for alpha-adrenoceptors. Affinity for alpha 1-and alpha 2-adrenoceptors was assessed by displacement of [3H]prasozin and [3H]clonidine, respectively. Lipophilicity of the aryl portion of the molecules, reflected by their partition coefficient between octanol and pH 7.4 buffer, correlated well with affinity at both receptor subtypes. Although some compounds showed nanomolar affinity for alpha-adrenoceptors, no subtype selectivity was observed. These results suggest that the aromatic ring enhances binding at both receptors chiefly through hydrophobic interactions and contributes little to subtype selectivity.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: J R
authors.initials: JR
authors.lastname: Huff
authors.forename: J J
authors.initials: JJ
authors.lastname: Baldwin
authors.forename: S J
authors.initials: SJ
authors.lastname: deSolms
authors.forename: J P
authors.initials: JP
authors.lastname: Guare
authors.forename: C A
authors.initials: CA
authors.lastname: Hunt
authors.forename: W C
authors.initials: WC
authors.lastname: Randall
authors.forename: W S
authors.initials: WS
authors.lastname: Sanders
authors.forename: S J
authors.initials: SJ
authors.lastname: Smith
authors.forename: J P
authors.initials: JP
authors.lastname: Vacca
authors.forename: M M
authors.initials: MM
authors.lastname: Zrada
mesh_terms: D000465:Algorithms; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D003000:Clonidine / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D011224:Prazosin / Q000378:metabolism; D011807:Quinolizines / Q000378:metabolism*; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015016:Yohimbine / Q000378:metabolism
chemical_list: D011807:Quinolizines; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; C038538:Wy 26703; D003000:Clonidine; D011224:Prazosin