An analysis of the stereochemical structure‐activity relationships of C‐methyl derivatives of the reversed ester of meperidine

Casy, A. F.

doi:10.1002/med.2610020204

Cited by 10 publications

(5 citation statements)

References 62 publications

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“…The results are thus consistent with the probable uptake conformation of pethidine reversed esters at opioid receptors (Casy 1982) and illustrate the fine degree of receptor discrimination for ligands in that the two antipodes differ merely in the relative placements of axial and equatorial methyl ar-to the basic centre. The findings also complement conclusions drawn from data upon 3,3-dimethyl analogues of the reversed ester of pethidine recently reported (Ahmed et al 1985).…”

Section: '4icationssupporting

confidence: 79%

“…The absolute configurations of the antipodes were established by X-ray analysis of the corresponding (-)-4-piperidinol hydrobromide. In antinociceptive tests on mice and rats, the (+)-2S,6S ester proved the more potent antipode by factors of at least 10 (rats) and 20 (mice), a result consistent with earlier proposals made about the probable uptake conformation of pethidine reversed esters at opioid receptors.In a recent analysis of the effect of alkyl substitution in the piperidine ring of 4-phenylpiperidine analgesics, a consistent stereochemical structure-activity pattern was developed on the basis of 4-phenylpiperidine ligands associating with opioid receptors in the form of equatorial 4-phenyl chair conformations (Casy 1982). The absolute orientations of methyl substituents that favour or have minor influence on the ligand-receptor interactions were identified and are as illustrated in I.…”

mentioning

confidence: 99%

“…In a recent analysis of the effect of alkyl substitution in the piperidine ring of 4-phenylpiperidine analgesics, a consistent stereochemical structure-activity pattern was developed on the basis of 4-phenylpiperidine ligands associating with opioid receptors in the form of equatorial 4-phenyl chair conformations (Casy 1982). The absolute orientations of methyl substituents that favour or have minor influence on the ligand-receptor interactions were identified and are as illustrated in I.…”

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confidence: 99%

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Racemic and optically active trans 2,6-dimethyl analogues of the reversed ester of pethidine

Cittern

et al. 1986

Journal of Pharmacy and Pharmacology

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The preparation and stereochemical characterization of (+/-)-1,trans 2,6-trimethyl-4-phenyl-4-propionoxypiperidine hydrochloride and its (+)- and (-)-antipodes are described. The absolute configurations of the antipodes were established by X-ray analysis of the corresponding (-)-4-piperidinol hydrobromide. In antinociceptive tests on mice and rats, the (+)-2S,6S ester proved the more potent antipode by factors of at least 10 (rats) and 20 (mice), a result consistent with earlier proposals made about the probable uptake conformation of pethidine reversed esters at opioid receptors.

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Section: '4icationssupporting

confidence: 79%

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confidence: 99%

mentioning

confidence: 99%

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Racemic and optically active trans 2,6-dimethyl analogues of the reversed ester of pethidine

Cittern

et al. 1986

Journal of Pharmacy and Pharmacology

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“…It has been assumed, based on the relative activities of the antipodes of P-prodine, that the most active antipode of the y-2,3-dimethyl derivative will be the one shown in Figure 6. 4 The conformational preferences of this compound are consistent with that of the other more active antipodes.…”

Section: Pharmacological Implicationssupporting

confidence: 63%

A study of the biologically active conformers for prodine opiates and their derivatives

Froimowitz¹,

Kollman²

1984

J Comput Chem

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Conformational energy calculations using the empirical MM2 (molecular mechanics 11) and semiempirical quantum mechanical PCILO (perturbative configuration interaction using localized orbitals) methods are reported for various prodine derivatives. These include 3-demethylprodine, a-prodine, /I-prodine, the a-2-methyl derivative, a-promedol, the y-2,3-dimethyl derivative, and y-isopromedol. The results are consistent with all of the compounds activating the opiate receptor in a phenyl equatorial conformation with optimum activity resulting from a particular orientation of the phenyl and propionoxyl groups. In disagreement with previous limited experimental data, a-promedol is found to prefer a phenyl equatorial conformer. I t is confirmed that, of the two mirror image phenyl equatorial conformers that are preferred for 3-demethylprodine, the more active prodines antipodes consistently prefer the one in which the phenyl orientation is the opposite (mirror image) of that found in morphine and in the preferred conformer of the morphine-like ( + )-phenylmorphan. This is a possible molecular basis for the nonmorphine-like effects that occur with the introduction of a phenyl meta hydroxyl into some prodine derivatives. I t is also suggested that the less active prodine antipodes, which have a morphine-like phenyl orientation, may act in a morphine-like manner a t opiate receptors.There are four major conformers that are possible for the prodines (Figs. 1-3) which are 4-phenylpiperidine opiate analgesics. First, the phenyl ring can be either in an equatorial or axial position on the piperidine ring. Secondly, there appear to be two preferred orientations of the phenyl and propionoxyl groups with each of the above due to the symmetry of the piperidine ring.' These are shown in Figure 1 for 3-demethylprodine in a phenyl equatorial conformation. In previously performed MM2 (molecular mechanics 11) calculations,' phenyl equatorial conformations were preferred by 1.9, 2.8, and 3.4 kcal/mol for 3-demethyl-, a-, and P-prodine in qualitative agreement with previous computational results using the semiempirical quantum mechanical PCILO method' and with experimental results. Somewhat unexpectedly, a phenyl equatorial conformation was calculated to be particularly preferred for P-prodine despite its having two axial piperidine substituents and only one equatorial one.' This was attributed to steric interactions among the three piperidine substituents in a phenyl axial conformer.With respect to the two preferred phenyl equatorial conformers, these have identical energies in 3-demethylprodine (Fig. 1) since the two are actually mirror images. However, with the addition of a 3-methyl group, as in a-and P-prodine (Figs. 2 and 3), one conformer becomes preferred.' For a-prodine, the energy difference between the two is only 0.5 kcal/mol. In contrast, the energy difference is a substantial 3.7 kcal/mol in P-prodine. Thus, in a-prodine, both of the phenyl equatorial conformers will be significantly populated, whereas P-prodine is conformat...

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“…Their solute molecular structures from ~3C NMR data have been reported by Casy, Ogungbamila & Rostron (1982) and the significance of their findings has been discussed by Casy (1982). The activity rankings of their propionate esters were established by Jacobson (1980) as y > a >/3.…”

Section: Introductionmentioning

confidence: 94%

Structure–potency relationships for three isomers of (±)-1,2,3-trimethyl-4-phenyl-4-piperidinol

Cygler¹,

Ahmed²

1984

Acta Crystallogr Sect B

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436 POLYTYPISM, TWINNING, AND DISORDER IN 2,2-AZIRIDINEDICARBOXAMIDE uniquely determined, because the alternative position is not compatible with the position of /:'5. Q3 may have one of four positions indicated by Q~, Q~i, Q~ii, Q~". If Q3 and P5 are fixed, Q4 is uniquely determined.Thus, only four stacking variants are in agreement with the observed lattice constants of form B.The atomic coordinates of form B (Br/ickner, 1982, deposited data) show that the variants (ii) and (iii) do not exist in form B, whereas both the variants (i) and (iv) are present. This results because:-it was impossible to decide between N and O ato'ms in the Fourier map; -variants (i) and (iv) are almost identical and may be transformed into each other by interchanging O atoms and NH2 groups.More precise information on the occurrence of (i) and (iv) in form B could be obtained from a detailed investigation of the distribution of the intensities in reciprocal space. Possible results are, for instance: -statistical occurrence of (i) and (iv) with approximately equal probabilities; -alternating occurrence of (i) and (iv); -the crystal consists of regions containing either only (i) or only (iv). The volume of the regions of type (i) and the volume of the regions of type (iv) are about the same. In both variants (i) and (iv) the two possible kinds of triples of layers are present. In (i) as well as in (iv) their proportion is 3:1 in favour of the triple existing in form A (see Fig. 3b).Concluding remark. The example discussed is also of interest in OD theory. No structure with a similar stacking of layers has been found so far. The combination of pairs of layers related by a centre of symmetry and pairs of layers related by a fourfold inversion axis is rather unusual. AbstractThe three isomers of the title compound, Ci4H21NO, are known to have propionate esters with potency rankings 3' > a >/3. The present X-ray analyses have shown their configurations to be: a-base, t-2-CH3, t-3-

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An analysis of the stereochemical structure‐activity relationships of C‐methyl derivatives of the reversed ester of meperidine

Cited by 10 publications

References 62 publications

Racemic and optically active trans 2,6-dimethyl analogues of the reversed ester of pethidine

Racemic and optically active trans 2,6-dimethyl analogues of the reversed ester of pethidine

A study of the biologically active conformers for prodine opiates and their derivatives

Structure–potency relationships for three isomers of (±)-1,2,3-trimethyl-4-phenyl-4-piperidinol

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