Investigation of the Role of Chirality in the Interaction with σ Receptors and Effect on Binge Eating Episode of a Potent σ₁ Antagonist Analogue of Spipethiane

Q3 · MEDICINE

Article

Author: Micioni Di Bonaventura, Emanuela ; Schepmann, Dirk ; Del Bello, Fabio ; Giorgioni, Gianfabio ; Cifani, Carlo ; Piergentili, Alessandro ; Giancola, JoLynn B. ; Vistoli, Giulio ; Micioni Di Bonaventura, Maria Vittoria ; Bonifazi, Alessandro ; Quaglia, Wilma ; Wünsch, Bernhard

The enantiomers of the potent σ₁ receptor antagonist (±)-1 were synthesized and evaluated for their affinity at σ₁, σ₂ receptors and dopamine transporter (DAT). Analogously to (±)-1, both of the enantiomers showed very high affinity for the σ₁ receptor and unprecedented selectivity over both the σ₂ receptor and DAT. The lack of enantioselectivity between (+)-1 and (-)-1 indicated that the center of chirality in the 2-position of the benzothiochromane nucleus does not play a crucial role in the interaction with any of the studied targets. Docking studies confirmed that the configuration of the enantiomers has only marginal effects on the molecular interactions with the σ₁ receptor. In in vivo studies in a female rat model of binge eating, (±)-1 dose-dependently decreased the binge eating episode elicited by a history of intermittent food restriction and stress, confirming and strengthening the important role played by the σ₁ receptor in bingeing-related eating disorders.

11 Feb 2010·Journal of Medicinal ChemistryQ1 · MEDICINE

Novel Highly Potent and Selective σ₁ Receptor Antagonists Related to Spipethiane

Q1 · MEDICINE

Article

Author: Zotti, Margherita ; Pigini, Maria ; Giannella, Mario ; Perfumi, Marina ; Piergentili, Alessandro ; Tucci, Paolo ; Del Bello, Fabio ; Quaglia, Wilma ; Amantini, Consuelo ; Santoni, Giorgio ; Palmery, Maura ; Mattioli, Laura

Conservative chemical modifications of the core structure of the lead spipethiane (1) afforded novel potent sigma(1) ligands. sigma(1) affinity and sigma(1/)sigma(2) selectivity proved to be favored by the introduction of polar functions (oxygen atom or carbonyl group) in position 3 or 4 (4-6) or by the elongation of the distance between the two hydrophobic portions of the molecule with the simultaneous presence of a carbonyl group in position 4 (8 and 9). The observed cytostatic effect against the human breast cancer cell line MCF-7/ADR, highly expressing sigma(1) receptors, and not against MCF-7, as well as the enhancement of morphine analgesia highlighted the sigma(1) antagonist profile of this series of compounds. In particular, due to its high sigma(1) affinity (pK(i) = 10.28) and sigma(1)/sigma(2) selectivity ratio (29510), compound 9 might be a novel valuable tool for sigma receptor characterization and a suitable template for the rational design of potential therapeutically useful sigma(1) antagonists.

01 Jan 2004·Journal of Molecular Graphics and Modelling

Molecular modeling of σ1 receptor ligands: a model of binding conformational and electrostatic considerations

Article

Author: Tamara M. Gund ; Jie Floyd ; Dawoon Jung

We have performed molecular modeling studies on several sigma 1 specific ligands, including PD144418, spipethiane, haloperidol, pentazocine, and others to develop a pharmacophore for sigma 1 receptor-ligand binding, under the assumption that all the compounds interact at the same receptor binding site. The modeling studies have investigated the conformational and electrostatic properties of the ligands. Superposition of active molecules gave the coordinates of the hypothetical 5-point sigma 1 pharmacophore, as follows: R1 (0.85, 7.26, 0.30); R2 (5.47, 2.40, -1.51); R3 (-2.57, 4.82, -7.10); N (-0.71, 3.29, -6.40); carbon centroid (3.16, 4.83, -0.60), where R1, R2 were constructed onto the aromatic ring of each compound to represent hydrophobic interactions with the receptor; and R3 represents a hydrogen bond between the nitrogen atom and the receptor. Additional analyses were used to describe secondary binding sites to electronegative groups such as oxygen or sulfur atom. Those coordinates are (2.34, 5.08, -4.18). The model was verified by fitting other sigma 1 receptor ligands. This model may be used to search conformational databases for other possibly active ligands. In conjunction with rational drug design techniques the model may be useful in design and synthesis of novel sigma 1 ligands of high selectivity and potency. Calculations were performed using Sybyl 6.5.

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Indication	Highest Phase	Country/Location	Organization	Date
Analgesia	Discovery	IT	University of Camerino	11 Feb 2010

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