- Conformation by NMR of two tetralin-based receptor ligands
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The conformation in solution of 1-phenyl-3-propionamido-1,2,3,4-tetrahydronaphthalene and 1-phenyl-3-(N,N-dimethylamino)-1,2,3,4-tetrahydronaphthalene has been determined by a combination of nuclear magnetic resonance measurements and molecular mechanics
- Gatti, Giuseppe,Piersanti, Giovanni,Spadoni, Gilberto
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- Synthesis and configuration determination of all enantiopure stereoisomers of the melatonin receptor ligand 4-phenyl-2-propionamidotetralin using an expedient optical resolution of 4-phenyl-2-tetralone
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An efficient and practical approach for the synthesis of all four stereoisomers of the MT2 melatonin receptor ligand 4-phenyl-2-propionamidotetralin (4-P-PDOT), each in enantiomerically pure form (ee > 99.9%), was developed. The strategy involved an optical resolution procedure of the key precursor (±)-4-phenyl-2-tetralone with the unusual resolving agent (S)-mandelamide, through the formation of four dihydronaphtalene-spiro-oxazolidin-4-one diastereomers. Interestingly, NMR experimental observations in combination with geometric calculations, provided unambiguous configuration assignments of all stereocenters of the key spiro stereoisomers. Cleavage of each single spiro diastereomer under acidic conditions gave enantiopure (R)- or (S)-4-phenyl-2-tetralone, which were then converted to each 4-P-PDOT single enantiomer by using stereoselective reactions.
- Lucarini, Simone,Bartolucci, Silvia,Bedini, Annalida,Gatti, Giuseppe,Orlando, Pierfrancesco,Piersanti, Giovanni,Spadoni, Gilberto
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p. 305 - 313
(2012/02/02)
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- Toward the definition of stereochemical requirements for MT 2-selective antagonists and partial agonists by studying 4-phenyl-2-propionamidotetralin derivatives
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New derivatives of 4-phenyl-2-propionamidotetralin (4-P-PDOT) were prepared and tested on cloned MT1 and MT2 receptors, with the purpose of merging previously reported pharmacophores for nonselective agonists and for MT2-selective antagonists. A 8-methoxy group increases binding affinity of both (±)-cis- and (±)-trans-4-P-PDOT, and it can be bioisosterically replaced by a bromine. Conformational analysis of 8-methoxy-4-P-PDOT by molecular dynamics, supported by NMR data, revealed an energetically favored conformation for the (2S,4S)-cis isomer and a less favorable conformation for the (2R,4S)-trans one, fulfilling the requirements of a pharmacophore model for nonselective melatonin receptor agonists. A new superposition model, including features characteristic of MT2- selective antagonists, suggests that MT1/MT2 agonists and MT2 antagonists can share the same arrangement for their pharmacophoric elements. The model correctly predicted the eutomers of (±)-cis- and (±)-trans-4-P-PDOT. The model was validated by preparing three dihydronaphthalene derivatives, either able or not able to reproduce the putative active conformation of 4-P-PDOT. (Figure presented)
- Bedini, Annalida,Lucarini, Simone,Spadoni, Gilberto,Tarzia, Giorgio,Scaglione, Francesco,Dugnani, Silvana,Pannacci, Marilou,Lucini, Valeria,Carmi, Caterina,Pala, Daniele,Rivara, Silvia,Mor, Marco
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experimental part
p. 8362 - 8372
(2012/02/14)
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- Diastereo- and enantioselective hydrogenation of a challenging enamide derived from 4-phenyl-2-tetralone: An appealing shortcut towards enantiopure cis-2-aminotetraline derivatives
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A clean, efficient, and diasteroselective (dr >95%) catalytic hydrogenation of the enamide N-(4- phenyl-3, 4-dihydronaphthalen-2-yl) propionamide (2a) using palladium on carbon is performed. This procedure provides the melatonin receptor ligand (±)-cis-4-
- Lucarini, Simone,Alessi, Matteo,Bedini, Annalida,Giorgini, Giorgia,Piersanti, Giovanni,Spadoni, Gilberto
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experimental part
p. 550 - 554
(2010/08/13)
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- An improved synthesis of cis-4-phenyl-2-propionamidotetralin (4-P-PDOT): A selective MT2 melatonin receptor antagonist
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A novel, efficient and diastereoselective procedure was developed for the gram-scale synthesis of cis-4-phenyl-2-propionamidotetralin (4-P-PDOT), a selective MT2 melatonin receptor antagonist. The synthetic strategy involved the conversion of 4
- Lucarini, Simone,Bedini, Annalida,Spadoni, Gilberto,Piersanti, Giovanni
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p. 147 - 150
(2008/09/20)
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- Synthesis of tritium labelled 4P-PDOT, a selective melatonin receptor antagonist
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A selective MT2 melatonin receptor antagonist, 4-phenyl-2-propionamidotetralin (4P-PDOT), was prepared as a tritium-labelled compound with high specific activity and radiochemical purity. Catalytic hydrogenation of a unique vinyl bromo precursor 10 was us
- Rhee, Sung W.,Tanga, Mary J.
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p. 925 - 932
(2007/10/03)
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- SUBSTITUTED 2-AMIDOTETRALINS AS MELATONIN AGONISTS AND ANTAGONISTS
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The present invention relates generally to compounds having melatonin receptor activities and in particular to substituted 2-amidotetralin derivatives; to pharmaceutical preparations comprising such compounds; and to methods for using these compounds as t
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- SUBSTITUTED 2-AMIDOTETRALINS AS MELATONIN AGONISTS AND ANTAGONISTS
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The present invention relates generally to compounds having melatonin receptor activities and in particular to substituted 2-amidotetralin derivatives; to pharmaceutical preparations comprising such compounds; and to methods for using these compounds as t
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