title: Synthesis, affinity at 5-HT2A, 5-HT2B and 5-HT2C serotonin receptors and structure-activity relationships of a series of cyproheptadine analogues.
abstract: 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-HT2A receptor were (pKi +/- 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-HT2B 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-HT2C receptor (pKi +/- 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 make feasible a common disposition to interact with all three 5-HT2 subtypes.
authors.affiliation: Department of Pharmacology, University of Santiago, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Honrubia
authors.forename: J
authors.initials: J
authors.lastname: Rodriguez
authors.forename: R
authors.initials: R
authors.lastname: Dominguez
authors.forename: E
authors.initials: E
authors.lastname: Lozoya
authors.forename: F
authors.initials: F
authors.lastname: Manaut
authors.forename: J A
authors.initials: JA
authors.lastname: Seijas
authors.forename: M C
authors.initials: MC
authors.lastname: Villaverde
authors.forename: J M
authors.initials: JM
authors.lastname: Calleja
authors.forename: M I
authors.initials: MI
authors.lastname: Cadavid
authors.forename: S
authors.initials: S
authors.lastname: Maayani
authors.forename: F
authors.initials: F
authors.lastname: Sanz
authors.forename: M I
authors.initials: MI
authors.lastname: Loza
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism; D002831:Choroid Plexus / Q000187:drug effects / Q000378:metabolism; D003533:Cyproheptadine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D004873:Ergolines / Q000378:metabolism; D005748:Gastric Fundus / Q000187:drug effects; D066298:In Vitro Techniques; D007650:Ketanserin / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D004873:Ergolines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D003533:Cyproheptadine; D007650:Ketanserin; C031649:mesulergine