On the conformation of naloxone, a narcotic antagonist

Karle, Isabella L.

doi:10.1107/s0567740874005620

Cited by 25 publications

(20 citation statements)

References 9 publications

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“…The X-ray structure was used as the starting structure for the computations of etorphine [6], oxymorphone [7], naloxone [8], and (+) p-prodine [9]. In all available solid-state structures, the piperidine ring is in the chair conformation and the N-substituent in an equatorial arrangement.…”

Section: Methods and Proceduresmentioning

confidence: 99%

Structural and electronic requirements for binding at the Mu–opioid receptor

Cometta-Morini

Loew

1992

Int J of Quantum Chemistry

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A pharmacophore for p-opioid receptor recognition based on a study of the fentanyl class of opioids has recently been characterized in our laboratories. To validate this pharmacophore, we have extended our theoretical studies to include four opiate analogs from structurally different classes and with high affinity but varying selectivity for the p-opiate receptor. An extensive conformational search of the flexible regions of these compounds has been carried out at two levels of approximations, using the CHARMm force field and the semiempirical molecular orbital method AM^. In a subsequent step, we have determined a series of structural, environmental, and electronic properties for each low-energy conformer of the analogs studied. All four analogs studied can assume a low-energy conformation in which at least three of the four stereoelectronic properties identified as modulators of recognition in the fentanyls are present in the same spatial arrangement. These results provide additional evidence for the plausibility of the proposed pharmacophore for p-opioid receptor recognition. 8

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Section: Methods and Proceduresmentioning

confidence: 99%

Structural and electronic requirements for binding at the Mu–opioid receptor

Cometta-Morini

Loew

1992

Int J of Quantum Chemistry

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“…Nuclear coordinates for morphine were taken from the study by Duchamp et al [21], and those for naloxone were obtained from the publication of Karle [22]. Other than changes in the positions of the hydrogen atoms and a 0.05-A lengthening of the allyl double bond in naloxone, idealization resulted in no significant modification of the solid-state structures.…”

Section: Computationsmentioning

confidence: 99%

Effects ofN-protonation on the electronic structure of morphine and naloxone

Cheney

Zichi

1981

Int. J. Quantum Chem.

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The FSGO molecular fragment technique has been employed to perform ab-initio SCF-MO calculations on morphine and naloxone in the free-base and N-protonated forms. Particular features of electronic structure which have been investigated are molecular-orbital (MO) density distributions, energies and ordering, as well as the correlation of specific orbitals between different molecular species. It has been found that high-energy occupied and low-energy unoccupied MOS are centered on the aromatic moiety of both drugs, enabling the ring to act either as an electron donor or as an acceptor in a charge-transfer interaction. Comparison of corresponding MOS in the free base and the acid cation of both morphine and naloxone demonstrates that the field of the cationic head causes a dramatic downward shift in orbital energies. Thus in the N-protonated drugs the acceptor capability of the benzene ring is greatly enhanced at the expense of its suitability as a donor. Furthermore, the ally1 group of naloxone becomes highly activated as an electron acceptor through N-protonation. Investigation of the molecular electrostatic potential of the free-base species has revealed preferred avenues of approach for electrophilic and nucleophilic entities. However, the N-protonated species shows no regions of attraction for electrophiles. In both the free base and the acid cation, the vicinities of the nitrogen atom and the 3-hydroxy group are found to be favorably disposed for electrostatic interactions with receptor entities possessing the proper charge or polarity. Based on the findings with regard to electronic structure, a simple model has been suggested to explain the binding of morphine and naloxone at the opioid receptor.

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“…Early X-ray crystallographic studies of morphines were performed on morphine (4) and codeine (5) with the objective of determining their molecular structure and absolute stereochemistry, respectively. More recently, refined structures of morphine (6) and some of its pharmacologically important derivatives, such as naloxone (7) and oxymorphone (a), have been obtained. The latter studies responded to the needs of medicinal chemists who attempted to explain the pharmacological effects of morphine agonists and antagonists in terms of the geometric (9,lO) and stereoelectronic (11)(12)(13)(14)(15)(16)(17)(18) features of these molecules.…”

mentioning

confidence: 99%

“…The latter studies responded to the needs of medicinal chemists who attempted to explain the pharmacological effects of morphine agonists and antagonists in terms of the geometric (9,lO) and stereoelectronic (11)(12)(13)(14)(15)(16)(17)(18) features of these molecules. After the publication of the refined structures of morphine (6) and naloxone (7), medicinal and quantum chemists started using these structures as an approximation of the structures of other morphine derivatives whose X-ray structures had not been determined (ll-L3, [15][16][17]. Such approximations were widely used and did not stimulate additional X-ray work in the morphine field.…”

mentioning

confidence: 99%