Chemical and Pharmaceutical Bulletin p. 842 - 848 (1997)
Update date:2022-08-16
Topics:
Honrubia, Maria Angeles
Jesus, Rodriguez
Dominguez, Rosa
Lozoya, Estrella
Manaut, Francesc
Seijas, Julio A.
Villaverde, Maria Carmen
Calleja, Jose M.
Cadavid, Maria Isabel
Maayani, Saul
Sanz, Ferran
Loza, Maria Isabel
Cyproheptadine is a drug that shows high affinity for type 2 (5-HT2) receptors. We studied a series of compounds obtained by modification of the tricyclic system of Cyp (dibenzocycloheptadiene): 2f (thioxanthene), 2g (xanthene), 2h (dihydrodibenzocycloheptadiene), 2j (diphenyl), 2i (fluorene), and 3b (phenylmethyl). Their activities at the rat cerebral cortex 5-HT(2A) receptor were (pK(i) ± S.E.M.): 8.80 ± 0.11 (Cyp), 8.60 ± 0.07 (2f), 8.40 ± 0.02 (2g), 8.05 ± 0.03 (2h), 7.87 ± 0.12 (2j), 6.70±0.02 (2i) and 6.45±0.02 (3b); those at the rat stomach fundus 5-HT(2B) receptor (pA2±S.E.M.) were: 9.14±0.25 (Cyp), 8.49±0.07 (2F), 7.58±0.58 (2g), 7.02±0.14 (2h), 6.07±0.20 (2j), and undetectable (21, 3b); and those at the pig choroidal plexus 5-HT(2C) receptor (pK(i)±S.E.M.) were: 8.71 ± 0.08 (Cyp), 8.68 ± 0.01 (20, 8.58 ± 0.20 (2g), 7.95 ± 0.05 (2h), 7.57 ± 0.04 (2j), 6.98 ± 0.04 (2i) and 6.63 ± 0.20 (3b). The slopes did not differ significantly from unity. The compounds exhibited the same order of activities at every type of receptor, and the most active molecules presented certain steric (butterfly conformation of the tricyclic system) and electrostatic (proton affinity on the top of the central rings) patterns. It is concluded that the activity of cyproheptadine derivatives at 5-HT2 receptors is related to these molecular features, which make feasible a common disposition to interact with all three 5-HT2 subtypes.
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