TY - JOUR
T1 - Pharmacological activities of optically pure enantiomers of the κ opioid agonist, U50,488, and its cis diastereomer
T2 - evidence for three κ receptor subtypes
AU - Rothman, Richard B.
AU - France, Charles P.
AU - Bykov, Victor
AU - De Costa, Brian R.
AU - Jacobson, Arthur E.
AU - Woods, James H.
AU - Rice, Kenner C.
PY - 1989/8/29
Y1 - 1989/8/29
N2 - De Costa et al. (FEBS Lett. 223, 335; 1987) recently described the synthesis of optically pure enantiomers of (±)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50,488). In the present study we examined the in vitro opioid receptor selectivity of (-)-(1S,2S)-U50,488, (+)-(1R,2R)-U50,488 and (±)-cis-3,4-di-chloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (the cis diasteromers of U50,488), as well as their pharmacological activities in rhesus monkeys. Using [3H]5α,7α,8β-(-)-N-methyl-N-[7-1-pyrrolidinyl)-1-oxaspiro (4,5)dec-8-yl]-phenyl-benzeneacetamide([3H]U69,593) to label κ binding sites of guinea pig membranes, the apparent dissociation constants of the enantiomers hadU50,488 were 0.89 and 299 nM, for the (S,S) and (R,R) enantiomers, respectively. The (-)-cis and (+)-cis diastereomers had apparent Kds of 167 and 2715 nM, respectively. Binding surface analysis of the interaction of (-)-(1S,2S)-U50,488 with κ binding sites labeled by [3H]bremazocine resolved two binding sites at which (-)-(1S,2S)-U50,488 had Kds of 30 and 10485 nM, respectively. The (±)-cis, (-)-cis and (+)-cis diastereomers of U50,488 (1 μM) did not inhibit [3H]bremazocine binding. Rhesus monkeys were trained to discriminate ethylketocyclazocine (EKC) and saline. All compounds tested substituted completely for EKC. The order of potency was (-)-(1S,2S)-U50,488 > (±)-U50,488 > (±)-cisdiastereomer of U50,488 > (+)-(1R,2R)-U50,488. In tests of analgesia, (-)-(1S,2S)-U50,488 was 2-4 times more potent than (±)-U50,488, while (±)-cis diastereomer of U50,488 and (+)-(1R,2R)-U50,488 were inactive at the highest doses tested (32 mg/kg). Taken collectively, these data indicate that the pharmacologically active enantiomer of U50,488 is (-)-(1S,2S)-U50,488, and provide preliminary evidence for three subtypes of κ binding sites in guinea pig brain.
AB - De Costa et al. (FEBS Lett. 223, 335; 1987) recently described the synthesis of optically pure enantiomers of (±)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50,488). In the present study we examined the in vitro opioid receptor selectivity of (-)-(1S,2S)-U50,488, (+)-(1R,2R)-U50,488 and (±)-cis-3,4-di-chloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (the cis diasteromers of U50,488), as well as their pharmacological activities in rhesus monkeys. Using [3H]5α,7α,8β-(-)-N-methyl-N-[7-1-pyrrolidinyl)-1-oxaspiro (4,5)dec-8-yl]-phenyl-benzeneacetamide([3H]U69,593) to label κ binding sites of guinea pig membranes, the apparent dissociation constants of the enantiomers hadU50,488 were 0.89 and 299 nM, for the (S,S) and (R,R) enantiomers, respectively. The (-)-cis and (+)-cis diastereomers had apparent Kds of 167 and 2715 nM, respectively. Binding surface analysis of the interaction of (-)-(1S,2S)-U50,488 with κ binding sites labeled by [3H]bremazocine resolved two binding sites at which (-)-(1S,2S)-U50,488 had Kds of 30 and 10485 nM, respectively. The (±)-cis, (-)-cis and (+)-cis diastereomers of U50,488 (1 μM) did not inhibit [3H]bremazocine binding. Rhesus monkeys were trained to discriminate ethylketocyclazocine (EKC) and saline. All compounds tested substituted completely for EKC. The order of potency was (-)-(1S,2S)-U50,488 > (±)-U50,488 > (±)-cisdiastereomer of U50,488 > (+)-(1R,2R)-U50,488. In tests of analgesia, (-)-(1S,2S)-U50,488 was 2-4 times more potent than (±)-U50,488, while (±)-cis diastereomer of U50,488 and (+)-(1R,2R)-U50,488 were inactive at the highest doses tested (32 mg/kg). Taken collectively, these data indicate that the pharmacologically active enantiomer of U50,488 is (-)-(1S,2S)-U50,488, and provide preliminary evidence for three subtypes of κ binding sites in guinea pig brain.
KW - 488
KW - Enantiomers
KW - Opiate receptors
KW - U-50,488
KW - U-69,593
KW - cis diastereomer of U-50
KW - κ Opioid receptors
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UR - http://www.scopus.com/inward/citedby.url?scp=0024446423&partnerID=8YFLogxK
U2 - 10.1016/0014-2999(89)90443-3
DO - 10.1016/0014-2999(89)90443-3
M3 - Article
C2 - 2553442
AN - SCOPUS:0024446423
SN - 0014-2999
VL - 167
SP - 345
EP - 353
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 3
ER -