Conformationally Constrained Butyrophenones with Mixed Dopaminergic (D₂) and Serotoninergic (5-HT_2A, 5-HT_2C) Affinities:  Synthesis, Pharmacology, 3D-QSAR, and Molecular Modeling of (Aminoalkyl)benzo- and -thienocycloalkanones as Putative Atypical Antipsychotics.

Abstract

Conformationally Constrained Butyrophenones with Mixed Dopaminergic (D 2 ) and Serotoninergic (5-HT 2A , 5-HT 2C ) Affinities: Synthesis, Pharmacology, 3D-QSAR, and Molecular Modeling of (Aminoalkyl)benzo-and -thienocycloalkanones as Putative Atypical Antipsychotics.

New Serotonin 5-HT2A, 5-HT2B, and 5-HT2CReceptor Antagonists: Synthesis, Pharmacology, 3D-QSAR, and Molecular Modeling of (Aminoalkyl)benzo and Heterocycloalkanones

“…A partial study of a limited number (28) of these compounds was reported in our preceding paper, which included the determination of 5-HT 2A and 5-HT 2C activities for 28 and 17 compounds, respectively. 64 Now, the set of compounds has been enlarged by studying 24 new compounds. The pharmacological activities (affinity and antagonistic activity) of the resulting 52 compounds were determined for both 5-HT 2A and 5-HT 2C receptors.…”

“…57 On the basis of the rhodopsin structural information 57,59 and of additional data coming from molecular biology experiments, [60][61][62][63] increasingly accurate models of GPCRs are being produced. 60,61,[63][64][65] These models can be useful for understanding ligand binding and receptor activation features.…”

“…In previous papers, 64,[76][77][78][79][80][81][82][83][84] we have reported different compounds potentially useful to study the structural and pharmacological features of the three 5-HT 2 receptor subtypes within a single chemical family, those of the butyrophenones.…”

Chiral Resolution, Pharmacological Characterization, and Receptor Docking of the Noncompetitive mGlu1 Receptor Antagonist (±)-2-Hydroxyimino- 1a,2-dihydro-1H-7-oxacyclopropa[b]naphthalene-7a-carboxylic Acid Ethyl Ester

“…According to this model the binding site of the CPCCOEt series not only involves residues in TMVII but also residues close to the extracellular surface of TMIII and TMVI. Similarly located binding sites were proposed for members of other GPCR families such as the A 3 adenosine 22 and 5-HT 2A serotonin 23 receptors which have no sequence similarity to mGlu receptors. For the adenosine receptor antagonists are thought to bind in a pocket formed by the TM domains III, V, and VI, whereas for the serotonin receptor TM domains III, VI, and VII are involved.…”

“…16 in analogy to other models proposed for GPCRs. [21][22][23] In brief, seven individual polyalanine standard R-helices of lengths 27, 27, 35, 25, 30, 30 and 24 were built and each was superimposed on the corresponding helix of the R-carbon template derived from the rhodopsin family of GPCRs. 17 The rms distances of superimposed C-R atoms of TM helices I-VII were 0.14, 0.79, 0.19, 0.13, 0.84, 1.35 and 0.12, respectively.…”