Derivatives of (R)-1,11-methyleneaporphine:: Synthesis, structure, and interactions with G-protein coupled receptors

The design and synthesis of a well-characterized novel ring system, (R)-lambda 1,11-methyleneaporphine [(R)-4], and 15 derivatives thereof are presented. The addition of various nucleophiles to (R)-lambda 1,11-carbonylaporphine [(R)-11] or to the 1,11-hydroxymethyleneaporphine epimers gave separable mixtures of epimers. The epimeric ratios obtained in most reactions seem to be a result of steric factors directing the nucleophilic attack. The structure of the epimers was determined by a combination of X-ray crystallography (5 derivatives), NMR spectroscopy, and chemical correlation. Interesting and diverse pharmacological profiles of the derivatives were revealed through binding studies at serotonin 5-HT7 and 5-HT1A receptors as well as at dopamine D-2A receptors. Two derivatives appeared to be selective 5-HT7 receptor antagonists. It is evident from our results that the novel ring system [(R)-4] provides a useful complement to other scaffolds available to medicinal chemists involved in studies of GPC receptors.