CY 208-243: a unique combination of atypical opioid antinociception and D1 dopaminomimetic properties.
Here we describe the potent antinociceptive action of the indolophenanthridine, CY 208-243, which has high affinities to the dopamine D1 binding and the opioid sites as well as to the 5-HT1A site. The antinociceptive action was comparable to that of morphine in most, but not all models of nociception, nevertheless, basic differences exist in its overall profile. Antagonism of CY 208-243's antinociceptive action was only possible with either high doses of naloxone or not at all and no cross-tolerance with morphine in CY 208-243 tolerant rats occurred. The biochemical basis for dependence liability may be absent and no opioid activity was observed in cultured hippocampal cells. Physical dependence did not occur after programmed administration in the rhesus monkey, nor did CY 208-243 cause respiratory depression in the rat (rather a stimulation). Lack of generalization in fentanyl-trained rats strongly suggests that CY 208-243 lacks opioid-like subjective cues. The coexistence of D1 dopaminergic and atypical opioid agonist properties represents a unique pharmacodynamic combination which is not shared with any other analgesic, and may provide safe and innovative pain therapy.
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R W
RW
Preclinical Research, Sandoz Ltd., Basel, Switzerland.
Büscher
H H
HH
Römer
D
D
Maurer
R
R
Enz
A
A
Gähwiler
B H
BH
Shearman
G T
GT
Seiler
M P
MP
Wüthrich
H
H
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004192:Discrimination, Psychological / Q000187:drug effects; D004361:Drug Tolerance; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000378:metabolism; D010146:Pain / Q000503:physiopathology; D010617:Phenanthridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*; D017447:Receptors, Dopamine D1; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D012119:Respiration / Q000187:drug effects; D019966:Substance-Related Disorders
D000700:Analgesics; D007211:Indoles; D010617:Phenanthridines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D011957:Receptors, Opioid; C054531:CY 208-243; D009270:Naloxone; D009020:Morphine