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Query: UNIPROT:P06889 (Mol)
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The structure-activity relationship studies that have been reported for cannabinoids suggest that 1) the conformation of the C-ring at the C9 position, 2) the A-ring phenolic hydroxyl, and 3) the hydrophobic side chain are important determinants for the production of analgesia, as well as other cannabinoid effects. However, either these previous structure-activity studies described for cannabinoid compounds have not been quantitative in nature or the prediction of the activity of known and unknown compounds based on molecular structure has not been tested in a comprehensive manner. In this study we describe a three-dimensional molecular modeling program using comparative molecular field analysis to derive quantitative structure-activity relationships fitting pharmacological potencies and binding affinities of cannabinoids. The analysis has proven to accurately fit the pharmacological activity of cannabinoid analogs, with cross-validated r2 values of greater than 0.3 and final analysis r2 values of greater than 0.88. Additionally, this study has further characterized the steric and electrostatic properties that account for the variations in their potency. The results from this study indicate that steric repulsion behind the C-ring is associated with decreased predicted binding affinity and pharmacological potency. On the other hand, the steric bulk of a side chain that is extended up to seven carbons contributes to predictions of increased binding affinity and potency. The electrostatic fields of cannabinoid analogs also contribute to the predicted in vitro and in vivo potencies. If the biological activities we have investigated are assumed to be the result of interaction with a single binding site, this method indicates the structural and physicochemical properties necessary for binding to the receptor and producing an effect. By defining cannabinoid binding affinity and behavioral activity pharmacophores, this method can be used for designing cannabinoid agonists and it is capable of predicting the activity of unknowns, thereby serving to facilitate rational drug design.
Mol Pharmacol 1991 Nov
PMID:Modeling the cannabinoid receptor: a three-dimensional quantitative structure-activity analysis. 194 37

The 4-(m-OH-phenyl)piperidines are a flexible fragment of the morphine/benzomorphan fused-ring opioids. Analogs in this family were synthesized with varying 4-alkyl substituents increasing in bulk from H through methyl, n-propyl, to t-butyl, each with the three N-substituents methyl, allyl, and phenethyl. These twelve compounds were evaluated for analgetic agonism in mice using two different models for antinociceptive activity, acetic acid writhing and tail-flick, the latter by both subcutaneous and intracerebroventricular routes of administration. Antagonism to morphine analgesia was also measured by the mouse tail-flick procedure. Binding affinities of these new analogs to different opioid receptor subtypes were determined. Energy conformational calculations on these compounds were also carried out using the empirical energy program called MOLMEC, in order to better understand how the 4-R substituents modulate receptor binding affinities and efficacies. The results obtained show that, in general, the compounds studied are mu-selective and vary in agonist potency from weak to morphine-like. Significant differences in rank order of analgetic potencies and their relationship to receptor affinities were obtained from the results of subcutaneous and intracerebroventricular administration. Results of energy-conformational calculations for twelve N-methyl compounds indicate that those with 4-alkyl substituents favor a common, non-morphine-like phenyl axial conformation. The 4-t-butyl compounds are, in fact, the first simple mono-alkyl-substituted 4-phenyl-piperidines predicted to definitely exist in a phenyl axial conformation, as confirmed by X-ray analysis. On the basis of this common phenyl axial conformation, the observed variation in mu receptor affinities and efficacies of the 4-methyl, 4-n-propyl, and 4-t-butyl compounds could be understood and the behavior of 4-ethyl and 4-isopropyl analogs predicted. Two equatorial conformers (rotamers) were found to be the preferred forms of the analogs with 4-R being H or an ester group, or with a 3-methyl group added trans (beta) to the 4-R group. Taking into account the rotational flexibility of these analogs, these two conformers could be used to understand differences in high and low efficacy compounds observed among analogs with preferred phenyl equatorial conformations. None of the analogs exhibit a fused-ring-like N-substituent modulation of efficacy. This result can, perhaps, be understood by their inability in any proposed conformer to totally mimic key receptor interactions of both the phenol-OH and N-substituent portions of the fused compounds.
Mol Pharmacol 1988 Sep
PMID:Structure-activity studies of morphine fragments. I. 4-alkyl-4-(m-hydroxy-phenyl)-piperidines. 284 51

1. Meptazinol is an interesting opioid-producing naloxone-reversible analgesia with few cardiovascular and respiratory effects. Recent studies indicate that mu 1 opioid receptors mediate meptazinol analgesia. Using a computerized autoradiographic subtraction technique, we have examined the regional distribution of meptazinol-sensitive [3H][D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAGO) binding and compared this with the distribution of mu 1 binding determined by competition with low [D-Ala2,D-Leu5]enkephalin (DADL) concentrations. 2. Meptazinol and DADL lowered [3H]DAGO to similar extents in most brain regions studied. The greatest levels of inhibition were observed in the periaqueductal gray, interpeduncular nucleus, thalamus, hypothalamus, and hippocampus. Low levels of inhibition were found in the temporal and frontal cortex. The correlation between the inhibition of [3H]DAGO binding by meptazinol and that by DADL was high (r = 0.83), consistent with the binding of meptazinol to mu 1 sites.
Cell Mol Neurobiol 1988 Dec
PMID:Quantitative autoradiographic distribution of meptazinol-sensitive binding sites in rat brain. 285 61

Extensive structure-activity relationship studies have demonstrated that specific requirements within the cannabinoid structure are necessary to produce potent analgesia. A three-point association between the agonist and the receptor mediating analgesia consists of: 1) the C ring hydroxyl, 2) the phenolic A ring hydroxyl, and 3) the A ring alkyl hydrophobic side chain. Potent tricyclic and bicyclic structures were synthesized as "nonclassical" cannabinoid analgetics that conform to this agonist-receptor three-point interaction model. At the cellular level, centrally active cannabinoid drugs inhibit adenylate cyclase activity in a neuroblastoma cell line. The structure-activity relationship profile for inhibition of adenylate cyclase in vitro was consistent with this same three-point association of agonists with the receptor. A correlation exists between the potency of drugs to produce analgesia in vivo and to inhibit adenylate cyclase in vitro. Enantio- and stereoselectivity were exhibited by the nonclassical cannabinoid compounds for both the analgetic response and the ability to inhibit adenylate cyclase. The magnitude of the enantioselective response was equal for both the biochemical and physiological endpoints. Based on the parallels in structure-activity relationships and the enantioselective effects, it is postulated that the receptor that is associated with the regulation of adenylate cyclase in vitro may be the same receptor as that mediating analgesia in vivo. A conceptualization of the cannabinoid analgetic receptor is presented.
Mol Pharmacol 1988 Mar
PMID:Nonclassical cannabinoid analgetics inhibit adenylate cyclase: development of a cannabinoid receptor model. 335 94

Azidothiorphan and its [14C]-labeled analogue have been developed as photoaffinity ligands for the active site of the neutral endopeptidase 24.11. In in vitro assays azidothiorphan inhibits the endopeptidase activity with a Ki of 0.75 nM. After ultraviolet irradiation the inhibitor binds irreversibly to the enzyme, and many factors suggest that the photolabeling occurs at the active site. The binding is accompanied by a loss of enzymatic activity, and the inclusion of the competitive inhibitor thiorphan protects the endopeptidase from this inactivation. In addition the binding of another competitive inhibitor [3H]N-[(R,S)-3-hydroxyaminocarbonyl-2-benzyl-1-oxopropyl]-glycine to the active site of endopeptidase-24.11 is inhibited after irradiation with azidothiorphan. Experiments with [14C]-azidothiorphan have shown that very little nonspecific binding of inhibitor to enzyme occurs and the the labeled probe remains bound under denaturing conditions. Azidothiorphan has also been found to produce a long-lasting naloxone-reversible analgesia after intracerebroventricular administration. The results show that azidothiorphan should prove useful both for structural studies and for investigations on the synthesis and turnover of the neutral endopeptidase-24.11.
Mol Pharmacol 1987 Nov
PMID:Irreversible photolabeling of active site of neutral endopeptidase-24.11 "enkephalinase" by azidothiorphan and [14C]-azidothiorphan. 347 79

Adult human hepatocytes in chemically defined culture conditions were incubated with morphine, heroin, meperidine, and methadone to investigate their potential hepatotoxicity to human liver. Cytotoxic effects were observed at about 100 times the plasma concentrations required to produce analgesia in human nonaddicts. Concentrations of 1 mM morphine, heroin, and meperidine reduced the glycogen content by 50%, while even 0.2 mM methadone produced a depletion of 70% after 24 h of treatment. Concentrations of 0.8 mM morphine and heroin, 0.4 mM meperidine, and 0.005 mM methadone inhibited the albumin synthesis by about 50% after 24 h of pretreatment. Intracellular glutathione was reduced to 50% of that of controls after 2-3 h of incubation with 2 mM morphine and 1 mM heroin, while 1 mM meperidine and 0.2 mM methadone produced a reduction of about 30% after 6 h incubation. The results show that therapeutic doses of the opioids is unlikely to produce irreversible damage to human hepatocytes, but opiate doses during tolerance or abuse may be a cause of liver dysfunction.
Mol Toxicol
PMID:Hepatotoxicity of the opioids morphine, heroin, meperidine, and methadone to cultured human hepatocytes. 350 97

Treating rat brain homogenates in vitro with oxymorphazone, the hydrazone derivative of oxymorphone, selectively inhibited in a long-acting manner the high-affinity (mu 1) binding of a number of 3H-opioids. This inhibition was not affected by extensive wash procedures which did effectively reverse classical opiates such as morphine and naloxone. A similar, persistent inhibition of binding was observed following in vivo administration of the drug. Both systemically and intracerebroventricularly, oxymorphazone produced a dose-dependent analgesia. Acutely, oxymorphazone (ED50, 0.6 mg/kg, sc) was approximately half as potent as oxymorphone (ED50, 0.3 mg/kg, sc) in the tail-flick assay. Administered at their ED50 doses, both compounds had the same durations of action. As the doses of drug were increased, however, the time course of oxymorphazone's analgesia became far more prolonged than that of oxymorphone. Following the administration of oxymorphazone (100 mg/kg), over 50% of the mice remained analgesic for greater than 24 hr, as opposed to none of the mice given oxymorphone (100 mg/kg). Oxymorphazone was far more potent intraventricularly (icv) than systemically. Fifty percent of the mice remained analgesic for greater than 20 hr following the injection of 40 micrograms/mouse (icv), whereas no mice remained analgesic after 20 hr following doses of oxymorphone as high as 50 micrograms/mouse (icv). These long-lasting analgesic actions of oxymorphazone could not be easily explained on pharmacokinetic grounds. Repeated administration of oxymorphazone daily for 3 days resulted in significant tolerance.
Cell Mol Neurobiol 1984 Mar
PMID:Oxymorphazone: a long-acting opiate analgesic. 620 57

Optical isomers of methotrimeprazine, an analgesic/neuroleptic, were investigated with respect to their ability to interact with six receptor types or subtypes. Bovine caudate nucleus tissue homogenates provided the dopamine, opiate, and serotonin receptor populations studied in these experiments. The radioligands used in saturation and binding competition experiments were tritiated dopamine, spiperone, dihydromorphine, 5-L-methionine enkephalin, naloxone, and 5-hydroxytryptamine. Saturation experiments verified acceptable performance of these in vitro receptor assay systems and indicated that a one-site binding model was adequate for each of these ligands under the experimental conditions employed. The competition experiments exhibited statistically significant (p less than 0.05) differences in isomeric effects only for dopamine and 5-hydroxytryptamine receptors. The more active isomer, levorotatory methotrimeprazine, was shown to be pharmacodynamically equivalent to chlorpromazine at these receptor types. When the magnitude of receptor stereoselectivity is plotted against an estimate of the more active isomer's affinity for that particular receptor, an excellent correlation is observed. This suggests that a high degree of stereoselectivity characterizes a highly specific drug/receptor interaction. These findings are compatible with the conclusion that methotrimeprazine does not produce analgesia via a direct action upon opiate receptors.
Mol Pharmacol 1982 Mar
PMID:Differential stereoselectivity of methotrimeprazine enantiomers for selected central nervous system receptor types. 628 67

We have identified a putative opioid receptor from mouse brain (KOR-3), belonging to the G protein-coupled receptor family, that is distinct from the previously cloned mu, delta, and kappa 1 receptors. Assignment of the clone to the opioid receptor family derives from both structural and functional studies. Its predicted amino acid sequence is highly homologous to that of the other opioid receptors, particularly in many of the transmembrane regions, where long stretches are identical to mu, delta, and kappa 1 receptors. Both cyclazocine and nalorphine inhibit cAMP accumulation in COS-7 cells stably expressing the clone. Northern analysis shows that the mRNA is present in brain but not in a number of other organs. Southern analysis suggests a single gene encoding the receptor. A highly selective monoclonal antibody directed against the native kappa 3 receptor recognizes, in Western analysis, the clone expressed in COS-7 cells. The in vitro translation product is also labeled by the antibody. Additional clones reveal the presence of several introns, including one in the second extracellular loop and another in the first transmembrane region. Antisense studies with an oligodeoxynucleotide directed against a region of the second extracellular loop reveal a selective blockade of kappa 3 analgesia in vivo that is not observed with a mismatch oligodeoxynucleotide based upon the antisense sequence. The mu, delta, and kappa 1 analgesia is unaffected by this antisense treatment. Antisense mapping of the clone downstream from the splice site in the first transmembrane region reveals that six different antisense oligodeoxynucleotides all block kappa 3 analgesia. In contrast, only one of an additional six different antisense oligodeoxynucleotides directed at regions upstream from this splice site is effective. This strong demarcation between the two regions raises the possibility of splice variants of the receptor. An additional clone reveals an insert in the 3' untranslated region. In conclusion, the antibody and antisense studies strongly associate KOR-3 with the kappa 3-opioid receptor, although it is not clear whether it is the kappa 3 receptor itself or a splice variant.
Mol Pharmacol 1995 Jun
PMID:Cloning and functional characterization through antisense mapping of a kappa 3-related opioid receptor. 760 58

Previous studies have shown that repeated opioid administration induces a tolerance to opioid, presumably due in part to an opioid-mediated compensatory increase in brain cholecystokinin (CCK) synthesis and/or release. In this study, in situ hybridization histochemistry was used to examine the effect of morphine tolerance on CCK gene expression in the amygdala of rat brains, by using a 35S-labeled synthetic oligonucleotide probe. CCK mRNA-positive neurons in normal rats were seen throughout the amygdaloid complex, with the most heavily labeled neurons in lateral, basal, and cortical nuclei, followed by the medial nucleus. Only a few labeled neurons were found in central and intercalated nuclei. The development of morphine tolerance in the rat was associated with increased hybridization signals for CCK mRNA in each subnucleus of the amygdala. Increases were seen in the numbers of positively labeled neurons and/or the numbers of hybridization grains per positively labeled neuron. Furthermore, differential patterns of increase in CCK mRNA in morphine tolerant rats occurred in different subnuclei of the amygdala, with the highest magnitude of increase in the cortical nucleus, followed in order by the medial, central, basal, intercalated and lateral nuclei. The present study demonstrated that repeated administration of morphine increased CCK gene expression in the amygdaloid complex, and suggested that the development of the tolerance to morphine analgesia is due, in part, to an increase in CCK activity in the amygdaloid complex. These findings substantiate the hypothesis that long-term administration of opioid may induce a compensatory increase in CCK synthesis and/or release, which then results in a progressive antagonism of opioid analgesia.
Brain Res Mol Brain Res 1994 Feb
PMID:Cholecystokinin gene expression in rat amygdaloid neurons: normal distribution and effect of morphine tolerance. 817 Mar 43


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