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)-lambda1,11-methyleneaporphine [(R)-4], and 15 derivatives thereof are presented. The addition of various nucleophiles to (R)-lambda1,11-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-HT(7) and 5-HT(1A) receptors as well as at dopamine D(2A) receptors. Two derivatives appeared to be selective 5-HT(7) 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.
Linnanen
T
T
Organic Pharmaceutical Chemistry, Uppsala University, Uppsala Biomedical Center, Box 574, SE-751 23 Uppsala, Sweden.
Brisander
M
M
Unelius
L
L
Sundholm
G
G
Hacksell
U
U
Johansson
A M
AM
D000818:Animals; D001060:Aporphines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D018360:Crystallography, X-Ray; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D013237:Stereoisomerism
C461188:1,11-methyleneaporphine; D001060:Aporphines; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; C104425:serotonin 7 receptor; D019204:GTP-Binding Proteins