SAR Morphine

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Structure activity relationship

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SAR of morphine Unit -V Alkaloids Dr.J.BelsenDavid, MPharm, PhD Associate Professor

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. Three major subtypes of opiate receptor μ (Mu, OP 3 ): the most important receptor, Encoded by the MOR-1 gene, sub typed into μ 1 and μ 2 . Agonists cause Supra–spinal & spinal analgesia, respiratory depression, euphoria, emetic effects, physical dependence and constipation. δ (Delta, OP 1 ): Encoded by the DOR-1 gene. Subtype into δ 1 and δ 2 . Spinal analgesia, GI motility, motor integration, cognitive functions, mood driven behavior are the agonist properties. κ (Kappa, OP 2 ): Learning & memory, spinal analgesia, sedation, neuroendocrine secretions.

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Morphine Ring numbering and nomenclature Based on phenanthrene thus these three rings are labeled A, B and C, other two are labeled D and E Morphine refers to rings A, B, C and D of morphine, hence, epoxymorphinans (more specifically the 4,5–α–epoxymorphinans) Rings B and E of morphine is termed Morphan, Ring A is aromatic and, thus, flat, Ring C is in the boat confirmation due to the double bond, Ring E is the nitrogen-containing piperidine ring, Ring D is the ether or epoxide The configuration at C9 is the most important, which determines the orientation and distance between the protonated nitrogen and the phenyl ring. In most cases the more active isomer is levorotatory. Usually the isomers with an S configuration are dextrorotatory General structure

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Modifications involve C3, C6, C7, C8, C14, and the piperidine Nitrogen The earliest molecular modifications were simple, such as esterification, etherification, and increasing the length of the N–substituent The net results were compounds with greater potency but also greater toxicities and additional liabilities and side effects Molecular modifications may be divided into three groups : Ring “A”, Ring “C” Ring “E”

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Ring “A” Modifications A free phenolic OH is optimal for μ receptor (analgesia) affinity, but will decrease LWPC and also leads to first pass glucuronidation leading to poorer oral bioavailablity. Example: morphine Conversion of the OH to ether causes decease in μ receptor affinity. Thus codeine is a prodrug for its analgesic effect. The larger the group the slower this proceeds and therefore, the larger the group the less μ receptor affinity However, etherification increases anti- tussive effectiveness and do not need to remove the alkyl group. Etherification also increases LWPC. The larger the lipophilic substituent the higher the LWPC and thus increased bioavailability and cannot glucuronidate. Example: codeine

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Conversion to an ester creates a prodrug which must be hydrolyzed at C3 to interact with the receptor. For diacetyl morphine (heroin) the ester at C6 does not have to be removed for the receptor interaction. The C3 is more susceptible to hydrolysis as phenyl is an electron withdrawer Such diacetyl derivative has increases LWPC and thus enhanced penetration through the BBB and thus euphoric rush which makes the compound more popular for abuse. Example: heroin Removal of ring D increases LWPC. So, in general, all else being equal, a morphinan is overall more potent than the corresponding epoxymorphinan. The ether bridge does not interact with the receptor so does not affect μ receptor affinity. Example: morphinans

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Ring C Modifications Natural conformation of C6 Hydroxyl is α. In this conformation it interacts, poorly, with a hydrophobic region of the receptor . The interaction is not favorable since the hydroxyl is not lipophilic . Addition of methyl group increases LWPC and μ receptor affinity. Example: heterocodeine, a structural isomer of codeine, which is more potent than even morphine Inversion to the β conformation increases μ receptor affinity as points away from the lipophilic region so does not interact unfavorably Removal of this OH increases μ receptor affinity it also removes unfavorable interaction with the hydrophobic site

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Oxidation d ecreases analgesic potency , which still possesses a polar oxygen, and apparently interacts more unfavorably with the hydrophobic region on the receptor Replacing hydroxyl with methyl or methylene increases μ receptor affinity, again, due to better hydrophobic interaction. Example: nalmefen. Introduction of additional OH at C14 increases μ receptor affinity due to an increased hydrogen bonding The C7, C8 (Δ7) olefinic bond saturation changes LWPC and μ receptor affinity. Saturation gives a slight increase in LWPC and also ring “C” goes from boat to chair conformation that changes the 3D position of C6 hydroxyl. This gets rid of the unfavorable hydrophilic–hydrophobic interaction . Thus, this also increases μ receptor affinity

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Saturation plus oxidation of C6 oxygen produces an increase in μ receptor affinity. The ketone is more rigid and held away from the hydrophobic region. May even interact with an adjacent hydrophilic region Removal of ring C increases LWPC. Removed C6 hydroxyl does not interact with the hydrophobic site on the receptor unfavorably so it increases μ receptor affinity. So, in general, all else being equal, benzmorphans are more potent than morphinans. Introduction of ring F increases LWPC. All else being equal, the oripavines are more potent than the epoxymorphinans. Example: etorphine

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Ring E Modifications “ R” configuration α to the N (C9) is optimal for μ receptor affinity Removal of N-methyl decreases LWPC, Quaternization decreases LWPC tremendously, N-oxide decreases LWPC which is more polar through resonance where there is an N + and O – form. Increasing size of N-alkyl decreases μ receptor affinity through steric hindrance but increases LWPC. As length of N-alkyl increases, μ receptor affinity decreases. Until the chain is about 5 carbons then μ receptor affinity starts to increase slightly due to induced-dipole, induced-dipole interaction with allosteric “A” site, which is a phenyl ring.

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Branching, unsaturation or strained ring structures in the N-alkyl substituent leads to antagonism or, at the very least, partial agonism, for at least one of the opioid receptors. (Nalorphine, Naltrexone ) Methylnaltrexone ( relistor , approved in Apr 2008) is a quaternized compound which act peripherally as µ- opioid antagonist. Thus It has been approved for treating (SC and oral) opioid drug induced constipation without affecting analgesia or precipitating the withdrawal syndromes of opioids . Substituents that are 3 carbons in length have higher μ receptor affinity as an antagonist than those with 4 carbons. Optimal antagonistic potency is obtained when the N–substituent chain is 3 carbons in length. Includes allyl and methyl isopropyl groups. Example: nalorphine Removal of C15 (breaking ring E) decreases μ receptor affinity

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Summarizing the Effects of altering chain length on N of morphine structure

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