Synthesis of benzocycloalkane derivatives as new conformationally restricted ligands for melatonin receptors.
Benzocycloalkane derivatives 1-4 were synthesized as new conformationally restricted melatoninergic ligands. They were prepared by the reaction of the ketones 5 with diethylcyanophosphonate and the reduction of the corresponding cyano compounds or by the Wittig reaction and Curtius degradation to obtain the amines 8. The 1-Cyanobenzocyclobutane derivative was obtained by the benzyne cyclisation reaction. The amines 8 were acylated with acetyl, propionyl or butyryl groups. The affinity of the compounds for chicken brain melatonin receptors was evaluated using 2-[125I]-iodomelatonin as the radioligand. The indanyl (2b,c), tetralin (3a-c) and benzocycloheptane (4c) derivatives were potent compounds with nanomolar affinity and an important enantioselectivity of the receptor was observed with the (+) enantiomers 2b and 3b.
Kloubert
S
S
CNRS-BIOCIS (URA 1843), Université de Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France.
Mathé-Allainmat
M
M
Andrieux
J
J
Sicsic
S
S
Langlois
M
M
D000473:Alkanes / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D002645:Chickens; D008024:Ligands; D008968:Molecular Conformation; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D044094:Receptors, Melatonin; D013329:Structure-Activity Relationship
D000473:Alkanes; D008024:Ligands; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin