Cyclic penicillamine containing enkephalin analogs display profound delta receptor selectivities.
The cyclic, penicillamine(beta, beta dimethylcysteine)-containing enkephalin analogs, [D-Cys2, L-Pen5]-and [D-Cys2, D-Pen5]enkephalin and the corresponding bis-penicillamine analogs, [D-Pen2, L-Pen5]-and [D-Pen2, D-Pen5]enkephalin were synthesized and evaluated for opioid activity in the guinea pig ileum (GPI) and mouse vas deferens (MVD) bioassays and in rat brain and neuroblastoma-glioma cell membrane binding assays. These analogs all displayed delta receptor selectivity as assessed by IC50(GPI)/IC50(MVD) ratios and by their relative potencies for displacing [3H]naloxone (NAL) vs. [3H] [D-Ala2, D-Leu5]enkephalin (DADLE) from rat brain membrane preparations. For [D-Pen2, L-Pen5]- and [D-Pen2, D-Pen5]enkephalin the observed IC50(GPI)/IC50 (MVD) ratios (1088 and 3164) and IC50NAL/IC50DADLE ratios (371 and 175) represent a vast improvement over previously reported delta receptor selective ligands.
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology*; D005910:Glioma / Q000378:metabolism; D006168:Guinea Pigs; D006822:Hybrid Cells / Q000378:metabolism; D007082:Ileum / Q000187:drug effects; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects*; D009447:Neuroblastoma / Q000378:metabolism; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects
D004745:Enkephalins; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; C040242:enkephalin, Cys(2)-Pen(5)-; C038233:enkephalin, Pen(2)-Cys(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-