Replacement of the constrained phenylalanine analogue 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in the opioid Dmt-Tic-Gly-NH-Bn scaffold by the 4-amino-1,2,4,5-tetrahydro-indolo[2,3-c]azepin-3-one (Aia) and 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffolds has led to the discovery of novel potent l-selective agonists (Structures 5 and 12) as well as potent and selective delta-opioid receptor antagonists (Structures 9 and 15). Both stereochemistry and N-terminal N,N-dimethylation proved to be crucial factors for opioid receptor selectivity and functional bioactivity in the investigated small pepti-domimetic templates. In addition to the in vitro pharmacological evaluation, automated docking models of Dmt-Tic and Dmt-Aba analogues were constructed in order to rationalize the observed structure activity data. (C) 2008 Elsevier Ltd. All rights reserved.
Conformationally constrained opioid ligands: The Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold / Steven, Ballet; Debby, Feytens; R., De Wachter; M., De Vlaeminck; Ewa D., Marczak; Severo, Salvadori; C., De Graaf; Didier, Rognan; Negri, Lucia; Lattanzi, Roberta; Lawrence H., Lazarus; Dirk, Tourwe; Gianfranco, Balboni. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - STAMPA. - 19:2(2009), pp. 433-437. [10.1016/j.bmcl.2008.11.051]
Conformationally constrained opioid ligands: The Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold
NEGRI, Lucia;LATTANZI, Roberta;
2009
Abstract
Replacement of the constrained phenylalanine analogue 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in the opioid Dmt-Tic-Gly-NH-Bn scaffold by the 4-amino-1,2,4,5-tetrahydro-indolo[2,3-c]azepin-3-one (Aia) and 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffolds has led to the discovery of novel potent l-selective agonists (Structures 5 and 12) as well as potent and selective delta-opioid receptor antagonists (Structures 9 and 15). Both stereochemistry and N-terminal N,N-dimethylation proved to be crucial factors for opioid receptor selectivity and functional bioactivity in the investigated small pepti-domimetic templates. In addition to the in vitro pharmacological evaluation, automated docking models of Dmt-Tic and Dmt-Aba analogues were constructed in order to rationalize the observed structure activity data. (C) 2008 Elsevier Ltd. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
