69160-63-0Relevant articles and documents
New benzomorphan derivatives of MPCB as MOP and KOP receptor ligands
Pasquinucci, Lorella,Iadanza,Marrazzo,Prezzavento,Ronsisvalle,Scoto,Parenti,De Luca,Ronsisvalle
experimental part, p. 813 - 824 (2009/04/04)
There is considerable interest in developing KOP Opioid receptor ligands as clinically useful analgesics. Moreover, compounds with mixed KOP receptor and mu-opioid peptide (MOP) receptor agonist/antagonist properties could have a better therapeutic potential. The benzomorphan-based synthetic ligands MPCB and CCB have been shown to bind KOP receptors with high affinity and selectivity. We report here a series of compounds synthesized to perform structure-affinity relationship (SAR) studies on MPCB. The aim of this study was to optimise KOP receptor-ligand interaction and to modulate MOP receptor selectivity. In the benzylamide analogue of MPCB (compound 9) the presence of a third aromatic nucleus, at an appropriate distance and conformation with respect to aromatic pharmacophoric residues, increased KOP receptor affinity by about 6-fold compared to MPCB (Ki = 35 nM and Ki = 240 nM, respectively). Instead, compound 28 with a tertiary amino group in the nitrogen substituent displayed a comparable KOP receptor affinity (Ki = 179 nM) but also high MOP receptor affinity (Ki = 45 nM). Thus, the present study shows that in benzomorphan-based ligands the presence of different functional groups in the nitrogen substituent, ranging from a positive charged amine to an additional aromatic ring, is able to promote the correct augment of aromatic pharmacophoric residues with MOP and KOP receptor types. Evaluation of docking simulations of compounds 9 and 28 into the KOP and MOP receptor displayed selective ligand interactions with the important amino acid residues Tyr320 (TMVII) and Trp318 (TMVII), respectively.
Synthesis and pharmacological evaluation of potent and enantioselective σ1 and σ2 ligands
Marrazzo, Agostino,Prezzavento, Orazio,Pasquinucci, Lorella,Vittorio, Franco,Ronsisvalle, Giuseppe
, p. 181 - 189 (2007/10/03)
In a previous study we found that substitutions of the (+)-cis-N-normetazocine nucleus of (+)-MPCB with 1-adamantanamine provide the compound (±)-10 with high affinity and selectivity for σ receptors. Starting with this result we have synthesized a new series of eight 1-phenyl-2-cyclopropylmethylamines structurally related to (±)-10, and binding affinities, with respect to σ1, σ2, opioid and dopaminergic D2 receptors, have been reported. All compounds showed a negligible opioid and dopaminergic affinity and high selectivity for σ receptors. Modifications on the amino moiety and methylcarboxyester group of 10 provide compounds with different σ1 and σ2 binding affinity and selectivity. Moreover, we have also synthesized the respective enantiomers of componds (±)-10 and (±)-18 in order to evaluate the enantioselectivity for σ1 and σ2 receptors. The binding data showed that carboxymethylester on the cyclopropane ring was more critical for enantioselectivity than the hydroxymethylenic group. In fact, the (-)-10 enantiomer showed a preference for σ1 whereas (+)-10 showed a preference for σ2.
1-Aryl-2-(aminomethyl)cyclopropanecarboxylic Acid Derivatives. A New Series of Potential Antidepressants
Bonnaud, Bernard,Cousse, Henri,Mouzin, Gilbert,Briley, Mike,Stenger, Antoine,et al.
, p. 318 - 325 (2007/10/02)
A series of 1-aryl-2-(aminomethyl)cyclopropanecarboxylic acid derivatives were synthesized and evaluated as potential antidepressants.Compounds with the Z configuration were synthesized from 1-aryl-2-oxo-3-oxabicyclohexane and those with E configuration from (E)-1-phenyl-2-(hydroxymethyl)cyclopropanecarboxylic acid.The compounds were evaluated in animal tests designed to reveal potential antidepressant activity and the existence of undesirable side effects.Several derivatives were more active than imipramine and desipramine.On the basis of its activity in pharmacological animal tests of antidepressant activity and its potential lack of side effects, 1-phenyl-1--2-(aminomethyl)cyclopropane hydrochloride, midalcipran (INN), was selected for further development.This compound is currently in phase III clinical evaluation.
