ABSTRACT
A series of tricyclic oxazines, namely, the 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, have been synthesized and assayed for dopamine agonist activity. One of the members of this series, compound (+)VII-15, was found to be a remarkably potent agonist in vivo when tested in the standard 6-hydroxydopamine lesioned rat assay. The absolute configuration of the compound corresponds to that found in the active isomer of apomorphine. Its activity at the alpha 2 receptor (vs. [3H]clonidine) is relatively low. It also failed to stimulate the synthesis of cAMP in the carp retina assay, thus giving the compound a highly selective profile in favor of the D2 receptor.
Subject(s)
Dopamine/analogs & derivatives , Oxazines/chemical synthesis , Receptors, Dopamine/metabolism , Animals , Apomorphine/metabolism , Cattle , Cerebral Cortex/metabolism , Clonidine/metabolism , Hydroxydopamines/pharmacology , Indicators and Reagents , Models, Molecular , Molecular Conformation , Motor Activity/drug effects , Oxazines/pharmacology , Oxidopamine , Rats , Receptors, Adrenergic, alpha/drug effects , Receptors, Adrenergic, alpha/metabolism , Receptors, Dopamine/drug effects , Rotation , Structure-Activity RelationshipABSTRACT
Synthesis of several members of the 9-oxaergoline ring system is presented. Both the C/D cis and the C/D trans isomers of 4,6,6a,8,9,10a-hexahydro-7-ethyl-7H-indolo[3,4-gh] [1,4]benzoxazine were prepared, and the C/D trans isomer was resolved into its optical isomers. The enantiomer having the highest affinity for the [3H]apomorphine binding site, (-)-trans-6-ethyl-9-oxaergoline [(-)-6b], was shown to have the same absolute configuration as the natural ergolines, namely, 6aR, 10aR. In vivo and in vitro pharmacological evaluation shows these 9-oxaergolines to possess potent dopamine agonist properties.
