Aspartic acid conjugates of 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1(3-aminophenyl)-2-(1-pyrrolidi nyl) ethyl]acetamide: kappa opioid receptor agonists with limited access to the central nervous system.
Aspartic acid conjugates of 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-aminophenyl)-2-(1-pyrrol idinyl) ethyl]acetamide (5) were synthesized and evaluated in mice for antinociceptive activity by intravenous and intracerebroventricular routes of administration. The intravenously-administered alpha-conjugate of L-Asp (2), its D-Asp diastereomer (3), and the beta -conjugate of L-Asp (4) were found to be 11-, 31-, and 40-fold, respectively, less effective than the parent ligand 1 (ICI 199,441) in producing central nervous system mediated antinociception in the mouse abdominal stretch assay. In addition, iv-administered 2 and 3 were found to also produce potent antinociception in the tonic phase of the mouse formalin assay, which is a model of tonic rather than acute pain. This study suggests that the attachment of a zwitterionic moiety to a position in the molecule that exhibits bulk tolerance is a viable strategy for the design of peripherally-selective and peripherally-active opioids.
Department of Medicinal Chemistry College of Pharmacy, University of Minnesota, Minneapolis 55455, USA.
A C
AC
Chang
A
A
Cowan
A E
AE
Takemori
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PS
Portoghese
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives*; D007536:Isomerism; D051379:Mice; D009619:Nociceptors / Q000187:drug effects; D011759:Pyrrolidines / Q000737:chemistry*; D017473:Receptors, Opioid, kappa / Q000819:agonists*
D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C058468:ICI 199441; D001224:Aspartic Acid