Abstract
(−)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). “Body” and “tail” interactions with opioid receptors (a subset of Portoghese’s message-address theory) were used for molecular modeling and simulations, where the “address” can be considered the “body” of the hydromorphone molecule and the “message” delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.
Highlights
It isN-substituents in the classical opioid-type of structure (e.g., 4,5-epoxyIt is well-known well-knownthat thatvarious various opioid-type of structure (e.g., 4,5morphinans, morphinans, 6,7-benzomorphans, 5-phenylmorphans) can change prototypicalN-methyl epoxymorphinans, morphinans, 6,7-benzomorphans, 5-phenylmorphans) can change prototypical substitutedsubstituted agonist opioids to opioids opioid antagonists.Most familiar, replacement of the N-methyl withN-methyl agonist to opioid antagonists.Most familiar, replacement of the NanN-allyl moiety in morphine and oxymorphone converted them to the antagonists nalorphine and methyl with an N-allyl moiety in morphine and oxymorphone converted them to the antagonists naloxone (Scheme 1)
(−)-N-substituted hydromorphone analogs with different substituents hydromorphone substituents on the N-phenethyl moiety were obtained by Non the
We found that a substituent, a chlorine atom, modified the activity of N-phenethylnorhydromorphone (S11), a potent full agonist with a DOR-MOR δ/μ potency ratio of 38.5, to a compound with a δ/μ potency ratio of 1.2, N-p-chloro phenethylnorhydromorphone (2i)
Summary
Introduction It isN-substituents in the classical opioid-type of structure (e.g., 4,5-epoxyIt is well-known well-knownthat thatvarious various opioid-type of structure (e.g., 4,5morphinans, morphinans, 6,7-benzomorphans, 5-phenylmorphans) can change prototypicalN-methyl epoxymorphinans, morphinans, 6,7-benzomorphans, 5-phenylmorphans) can change prototypical substitutedsubstituted agonist opioids to opioids opioid antagonists.Most familiar, replacement of the N-methyl withN-methyl agonist to opioid antagonists.Most familiar, replacement of the NanN-allyl moiety in morphine and oxymorphone converted them to the antagonists nalorphine and methyl with an N-allyl moiety in morphine and oxymorphone converted them to the antagonists naloxone (Scheme 1). N-substituents in the classical opioid-type of structure It is well-known well-knownthat thatvarious various opioid-type of structure (e.g., 4,5morphinans, morphinans, 6,7-benzomorphans, 5-phenylmorphans) can change prototypical. N-methyl epoxymorphinans, morphinans, 6,7-benzomorphans, 5-phenylmorphans) can change prototypical substitutedsubstituted agonist opioids to opioids opioid antagonists. Replacement of the Nan. N-allyl moiety in morphine and oxymorphone converted them to the antagonists nalorphine and methyl with an N-allyl moiety in morphine and oxymorphone converted them to the antagonists naloxone (Scheme 1)
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