title: 3D pharmacophore models for 1,2,3,4-tetrahydroisoquinoline derivatives acting as anticonvulsant agents.
abstract: A 3D pharmacophore model predicting anticonvulsant activity was obtained for a series of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives recently disclosed as a new class of noncompetitive AMPA receptor antagonists. The training set included 17 compounds with varying potency against audiogenic seizures in DBA/2 mice. The best statistical hypothesis, generated with the HypoGen module of Catalyst 4.9, consisted of five features: two hydrogen bond acceptors, two hydrophobic features, and one hydrophobic aromatic region, providing a model with a correlation coefficient of 0.919. The obtained model was an efficient tool in the design of some new anticonvulsant agents containing the tetrahydroisoquinoline scaffold. Moreover, in order to explain the different degree of efficacy of the newly designed N-substituted derivatives, excluded volumes were also considered.
authors.affiliation: Dipartimento Farmaco-Chimico, Università di Messina, Messina, Italy. ldeluca@pharma.unime.it
authors.forename: Laura
authors.initials: L
authors.lastname: De Luca
authors.forename: Rosaria
authors.initials: R
authors.lastname: Gitto
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Barreca
authors.forename: Roberta
authors.initials: R
authors.lastname: Caruso
authors.forename: Silvana
authors.initials: S
authors.lastname: Quartarone
authors.forename: Rita
authors.initials: R
authors.lastname: Citraro
authors.forename: Giovambattista
authors.initials: G
authors.lastname: De Sarro
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D020195:Epilepsy, Reflex / Q000139:chemically induced / Q000517:prevention & control; D005260:Female; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D023421:Models, Animal; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; C109853:G 1617; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C061950:GYKI 52466; D001569:Benzodiazepines; C085266:talampanel