Aporphines. 36. Dopamine Receptor Interactions of Trihydroxyaporphines. Synthesis, Radioreceptor Binding, and Striatal Adenylate Cyclase Stimulation of 2,10,11-Trihydroxyaporphines in Comparison with Other Hydroxylated Aporphines

Article abstract of DOI:10.1021/jm00144a014

The presence of the A ring of aporphines and the addition of substituents to it and to other portions of the aporphine ring systems can extend explorations of the dimensions and other characteristics of the dopamine receptor.Accordingly, the synthesis and some physical and pharmacological properties of a series of (-)-2,10,11-trihydroxyaporphines (3a-g) are described.Structure-activity relationships among mono-, di-, and trihydroxyaporphines were evaluated against the high-affinity (nanomolar) binding of <3H>apomorphine (APO) and <3H>spiroperidol (SPR) with a subcellular fraction (P₄) of caudate nucleus from bovine brain.In addition, DA-sensitive adenylate cyclase activity was evaluated in homogenates of rat brain striatal tissue.The rank order of displacement of <3H>APO by potent aporphines (IC50<*>30 nM) correlated approximately with their ability to stimulate cyclic AMP synthesis.Potency orders against the two ligands were dissimilar; for example, increasing the size of N⁶-alkyl substituents increased potency vs. <3H>SPR but not vs. <3H>APO binding.Moreover, <3H>SPR binding correlated poorly with cyclase activity or <3H>APO binding, suggesting a closer relationship of <3H>APO binding to dopamine-sensitive adenylate cyclase activity.