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J Med Chem ; 55(14): 6352-62, 2012 Jul 26.
Article in English | MEDLINE | ID: mdl-22734622

ABSTRACT

3-Iodobenzoylnaltrexamide 1 (IBNtxA) is a potent analgesic acting through a novel receptor target that lack many side-effects of traditional opiates composed, in part, of exon 11-associated truncated six transmembrane domain MOR-1 (6TM/E11) splice variants. To better understand the SAR of this drug target, a number of 4,5-epoxymorphinan analogues were synthesized. Results show the importance of a free 3-phenolic group, a phenyl ring at the 6 position, an iodine at the 3'or 4' position of the phenyl ring, and an N-allyl or c-propylmethyl group to maintain high 6TM/E11 affinity and activity. 3-Iodobenzoylnaloxamide 15 (IBNalA) with a N-allyl group displayed lower δ opioid receptor affinity than its naltrexamine analogue, was 10-fold more potent an analgesic than morphine, elicited no respiratory depression or physical dependence, and only limited inhibition of gastrointestinal transit. Thus, the aryl-naloxamide scaffold can generate a potent analgesic acting through the 6TM/E11 sites with advantageous side-effect profile and greater selectivity.


Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Exons/genetics , Opiate Alkaloids/chemical synthesis , Opiate Alkaloids/pharmacology , Receptors, Opioid, mu/genetics , Receptors, Opioid, mu/metabolism , Amides/chemistry , Amides/metabolism , Analgesics/chemical synthesis , Analgesics/chemistry , Analgesics/metabolism , Analgesics/pharmacology , Animals , Behavior, Animal/drug effects , Brain/drug effects , Brain/metabolism , Cell Line , Chemistry Techniques, Synthetic , Male , Mice , Opiate Alkaloids/chemistry , Opiate Alkaloids/metabolism , Protein Isoforms/chemistry , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Structure, Tertiary , Receptors, Opioid, mu/chemistry , Structure-Activity Relationship
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