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 (2i, 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 (2f), 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 features, which make feasible a common disposition to interact with all three 5-HT₂ subtypes.