96193-27-0Relevant academic research and scientific papers
Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists
Moir, Elizabeth M.,Yoshiizumi, Kazuya,Cairns, Jim,Cowley, Phillip,Ferguson, Morag,Jeremiah, Fiona,Kiyoi, Takao,Morphy, Richard,Tierney, Jason,Wishart, Grant,York, Mark,Baker, James,Cottney, Jean E.,Houghton, Andrea K.,McPhail, Petula,Osprey, Andrew,Walker, Glenn,Adam, Julia M.
scheme or table, p. 7327 - 7330 (2011/01/12)
Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo.
BICYCLIC NONANE AND DECANE COMPOUNDS HAVING DOPAMINE RECEPTOR AFFINITY
-
, (2008/06/13)
Described herein are D4 receptor-selective compounds of the general formula: STR1 wherein: A and B are independently selected, substituted or unsubstituted, unsaturated 5-or 6-membered, homo-or heterocyclic rings;X 1 is selected from O, S, SO, SO 2, CH. sub.2, C=O, CH--OH, CH--N(C 1-4 alkyl) 2, C= CHCl, and C=CHCN;X 2---is selected from N= , CH. sub.2--, CH= and C(O)--;n is 1 or 2; R 1 is selected from H and the α-carbon side chain of an amino acid;R 2 and R 3 are selected independently from H, OH,--NH 2,--C(O)NH 2 =O, =S,halo, cyano, C 1-9 alkyl, C 1-9 alkoxy, C 1-4 alkylS--, C 1-4 alkylSO--, C 1-4 alkylSO 2--, phenoxy, benzyloxy and piperonyloxy; andH* is in either the R-or the S-configuration,and acid addition salts, solvates and hydrates thereof.Their use as ligands for dopamine receptor identification and in a drug screening program, and as pharmaceuticals to treat indications in which the D4 receptor is implicated, such as schizophrenia, is also described.
BICYCLIC NONANE AND DECANE COMPOUNDS HAVING DOPAMINE RECEPTOR AFFINITY
-
, (2008/06/13)
Described herein are D4 receptor-selective compounds of the general formula: STR1 wherein: A and B are independently selected, optionally substituted, saturated or unsaturated 5-or 6-membered, homo-or heterocyclic rings;X 1 is selected from CH 2, O, NH, S, C=O, CH--OH, CH--N(C 1-4 alkyl) 2, C=CHCl, C= CHCN, N-C 1-4 alkyl, N-acetyl, SO 2 and SO;X. sub.2---is selected from N=, CH 2--, CH=, C(O)--, O--, and S--;n is 1 or 2;R 1 is selected from H and an amino acid side chain;R 2 is selected from H, OH, C 1-9 alkyl, C 1-9 alkoxy, and benzyloxy; andR 3 is selected from H, OH, halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenoxy, benzyloxy, =O, =S, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonyl, C 1-4 alkylthio, amino, and aminocarbonyl;and acid addition salts, solvates and hydrates thereof. Their use as ligands for dopamine receptor identification and in a drug screening program, and as pharmaceuticals to treat indications in which the D4 receptor is implicated, such as schizophrenia, is also described.
Synthesis and Evaluation of Conformationally Restricted N--N-methyl-2-(1-pyrrolidinyl)ethylamines at ? Receptors. 2. Piperazines, Bicyclic Amines, Bridged Bicyclic Amines, and Miscellaneous Compounds
Costa, Brian R. de,He, Xiao-shu,Linders, Joannes T.M.,Dominguez, Celia,Gu, Zi Qiang,et al.
, p. 2311 - 2320 (2007/10/02)
As a continuation of our earlier study (J.Med.Chem. 1992, 35, 4334-4343) we conformationally restricted the ?-receptor ligand 2-(1-pyrrolidinyl)-N--N-methylethylamine (1) by incorporating it into a series of homologous piperazines 3-9 and homopiperazines 10 and 11, diazabicyclononanes and decanes, bridgehead bicyclooctanes and nonanes as well as other miscellaneous compounds. ?-Receptor binding affinites were obtained using (+)-pentazocine in guinea pig brain membrane ?1 sites.The studies suggest that the nitrogen lone pair orient ation found in the piperazines affords the strongest binding interaction.Other nitrogen lone pair orientations or compounds representing unlikely staggered conformations of 1 -1,4-diazabicyclononane (16)> show very weak ? interaction.Comperison of the binding data of different N-substituted homologues of 1 with those of the 1--4-alkylpiperazines suggests that the two nitrogen atoms of 1 are working in opposition to one another in terms of their sensitivity to steric bulk.The high binding affinity of the 1,4-diazabicyclononanes 12 suggests that these may approximate the methyl and pyrrolidine ring conformations found in 1 when it is bound to the ? receptor.Compound 12 exhibited a 4-fold enantioselectivity favoring (+)-12.The synthesis of 6,7-dichloro-2-amino>tetralin (19) and its desmethyl derivative 20 permitted constraint of the 3,4-dichlorophenyl and N-methyl moieties of 1 into a gauche orientation.The binding data suggests that this conformation in 1 favors strong binding interaction at ?-receptors. ?-Receptor K1's ra nged from 0.55 nM for 1--4-n-butylpiperazine (7) to 654 nM for 16.Overall comparison of the results indicate that 1 is subject to considerable conformational freedom and suggests that the ?-receptor is not subject to rigid stereochemical restraints with 1.These results add to our earlier study where we restrained 1 using simple monocyclic heterocycles.
