AIM: Opioid-induced bowel syndromes deteriorate patients' quality of life and may lead to nonadherence to opioid schedule and under-treatment of pain. The objective was to characterize the pharmacological profile of 17-cyclopropylmethyl-6,7-didehydro-4,5α-epoxy-6'-ethoxycarbonyl-3,14-dihydroxyindolo [2',3'-6,7]morphinan (TAN-452), a novel peripherally acting opioid receptor antagonist. MAIN METHODS: The in vitro binding affinity for the μ-, δ-, and κ-opioid receptors (MOR, DOR, and KOR) and the inhibition of [35S]GTPγS binding were examined using membrane preparations from recombinant human (h) MOR, DOR, or KOR expressing cell. In vivo assays were performed to determine the inhibitory effect of TAN-452 on morphine-induced emesis (anti-emetic activity) in ferrets, morphine-induced inhibition of small intestinal transit (anti-constipation activity) in rats, and morphine-induced antinociception (anti-analgesic activity) in rats. A pharmacokinetic study was also performed. KEY FINDINGS: The binding affinities of TAN-452 (Ki) were 36.56 ± 1.48 nM, 0.47 ± 0.09 nM, and 5.31 ± 1.80 nM for hMOR, hDOR, and hKOR, respectively. Its antagonistic activities (Kb) were 9.43 ± 0.58 nM, 0.21 ± 0.06 nM, and 7.18 ± 0.75 nM, respectively. The ED50 values (95% Confidence interval) were <1.0 mg/kg p.o. and <0.3 mg/kg s.c. for anti-emetic activity, 9.45 (4.09, 47.79) mg/kg p.o. and 0.52 (0.10, 1.08) mg/kg s.c. for anti-constipation activity, and >300 mg/kg p.o. and >30 mg/kg s.c. for anti-analgesic activity. The pharmacokinetic study demonstrated low brain penetrability of TAN-452. SIGNIFICANCE: TAN-452 is a peripherally acting opioid receptor antagonist with selectivity for DOR that attenuates morphine-induced side effects, such as nausea, vomiting, and constipation, without affecting pain control.
AIM: Opioid-induced bowel syndromes deteriorate patients' quality of life and may lead to nonadherence to opioid schedule and under-treatment of pain. The objective was to characterize the pharmacological profile of 17-cyclopropylmethyl-6,7-didehydro-4,5α-epoxy-6'-ethoxycarbonyl-3,14-dihydroxyindolo [2',3'-6,7]morphinan (TAN-452), a novel peripherally acting opioid receptor antagonist. MAIN METHODS: The in vitro binding affinity for the μ-, δ-, and κ-opioid receptors (MOR, DOR, and KOR) and the inhibition of [35S]GTPγS binding were examined using membrane preparations from recombinant human (h) MOR, DOR, or KOR expressing cell. In vivo assays were performed to determine the inhibitory effect of TAN-452 on morphine-induced emesis (anti-emetic activity) in ferrets, morphine-induced inhibition of small intestinal transit (anti-constipation activity) in rats, and morphine-induced antinociception (anti-analgesic activity) in rats. A pharmacokinetic study was also performed. KEY FINDINGS: The binding affinities of TAN-452 (Ki) were 36.56 ± 1.48 nM, 0.47 ± 0.09 nM, and 5.31 ± 1.80 nM for hMOR, hDOR, and hKOR, respectively. Its antagonistic activities (Kb) were 9.43 ± 0.58 nM, 0.21 ± 0.06 nM, and 7.18 ± 0.75 nM, respectively. The ED50 values (95% Confidence interval) were <1.0 mg/kg p.o. and <0.3 mg/kg s.c. for anti-emetic activity, 9.45 (4.09, 47.79) mg/kg p.o. and 0.52 (0.10, 1.08) mg/kg s.c. for anti-constipation activity, and >300 mg/kg p.o. and >30 mg/kg s.c. for anti-analgesic activity. The pharmacokinetic study demonstrated low brain penetrability of TAN-452. SIGNIFICANCE: TAN-452 is a peripherally acting opioid receptor antagonist with selectivity for DOR that attenuates morphine-induced side effects, such as nausea, vomiting, and constipation, without affecting pain control.