Synthesis of 2-amido-2,3-dihydro-1H-phenalene derivatives as new conformationally restricted ligands for melatonin receptors.
Tetrahydroanthracene, tetrahydrophenanthrene, and tetrahydrophenalene moieties were used to design novel constrained melatoninergic agents. Compounds 1 and 2 were synthesized from the cyclization of the aryl succinic acids 6a,b followed by catalytic reduction, Curtius degradation to the amino derivatives, and acetylation. The phenalene derivatives 3 were prepared by cyclization of the aza lactones of the corresponding alpha-N-acetyl amino acids. The ketone derivatives were reduced directly by catalytic hydrogenation to produce the compounds 3. The different compounds were evaluated in vitro in binding assays using 2-[125I] iodomelatonin and chicken brain membranes. Melatonin and 2-acetamido-8-methoxytetralin were used as the reference compounds. The results showed the superiority of the dihydrophenalene framework 3 over those of tetrahydroanthracene and tetrahydrophenanthrene. 3a had relatively good affinity for melatonin receptors (Ki = 28.7 nM). Introduction of an additional methoxy group gave a derivative (3c) with nanomolar affinity (Ki = 0.7 nM), confirming the existence of a secondary binding site in the receptor which has been described previously. An increase in the affinity was also observed with the propionamido derivative 3e (Ki = 6.0 nM). The potential agonist properties of the compound 3e were evaluated on the dermal melanocytes of Xenopus laevis tadpoles. At the concentration of 2.3 nM (5 x Ki), melatonin gave a melanophore index value of 1. Similarly to melatonin, 3e was shown to be a potent agonist of the melanosome aggregation.
Mathé-Allainmat
M
M
CNRS-BIOCIS, URA 1843, Faculté de Pharmacie, Châtenay-Malabry, France.
Gaudy
F
F
Sicsic
S
S
Dangy-Caye
A L
AL
Shen
S
S
Brémont
B
B
Benatalah
Z
Z
Langlois
M
M
Renard
P
P
Delagrange
P
P
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008544:Melanocytes / Q000187:drug effects* / Q000502:physiology; D008547:Melanophores / Q000187:drug effects; D008550:Melatonin / Q000378:metabolism; D008968:Molecular Conformation; D015394:Molecular Structure; D011083:Polycyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000378:metabolism*; D044094:Receptors, Melatonin; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D000577:Amides; D008024:Ligands; D011083:Polycyclic Compounds; D011956:Receptors, Cell Surface; D044094:Receptors, Melatonin; D008550:Melatonin