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Publications (19)36.44 Total impact

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    ABSTRACT: A series of 5 spiro compounds, a new class of conformationally restricted analogs of 4-alkyl-4-(m-OH-phenyl) piperidines, have been synthesized and their affinities for μ, δ and κ opioid receptor sites and in vivo analgetic activities determined. All compounds show rather low affinities for the 3 receptors, with some modulation by the N-substituent and by the position of the phenolic group. To help understand the origin of this poor affinity compared to the unrestricted 4-alkyl-4-phenyl piperidines, energy conformation calculations were performed which indicated that all the analogs favor a phenyl equatorial over a phenyl axial conformer. Significant differences in the lowest energy conformation were found between these spiro analogs and both morphine and 4-n-propyl-4-(m-OH-phenyl) piperidines, 18 and 19 which are conformationally unrestricted, closely related analogs with high μ-affinity. These differences could account for their lower affinities. To continue the search for more active members of the family, structure variations which favor a phenyl-axial conformation have been identified and proposed for further study.RésuméUne série de cinq spiro-[tétraline-1,4′-pipéridines], une nouvelle classe d'analogues à conformation restreinte des 4-alkyl-4-(m-OH-phényl) pipéridines ont été synthétisées, et leurs affinités aux sites récepteurs opioïdes μ, δ et κ ainsi que leurs activités analgésiques ont été déterminées. Tous les composés montrent des affinités plutôt faibles pour les trois récepteurs, avec quelque modulation par le substituant de l'azote et par la position du groupe phénolique. Pour aider à comprendre l'origine de cette faible affinité, des calculs de l'énergie de conformation ont été effectués indiquant que les cinq analogues favorisent un phényle équatorial plutôt qu'un phényle axial. Des différences considérables de conformation d'énergie la plus faible ont été trouvées entre ces analogues et la morphine ainsi que les 4-n-propyl-4-(m-OH-phényl) pipéridines, proches analogues à conformation non restreinte avec forte affinité μ, qui pourraient expliquer leurs plus faibles affinités. Pour poursuivre la recherche de membres plus actifs de cette famille, des composés qui favorisent une conformation à phényle axial ont été identifiés et proposés pour des études supplémentaires.
    European Journal of Medicinal Chemistry. 11/1991; 26(8):775-785.
  • Progress in clinical and biological research 02/1989; 289:411-32.
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    ABSTRACT: A series of 2-methyl-3-carbethoxy-3-(m-hydroxyphenyl)piperidine opiates (13a-d) with N-substituent variations have been synthesized, and their receptor affinities and in vivo agonist and antagonist activities and energy-conformational profiles have been determined. These are racemates of the alpha-epimer at the C-2 position, with a methyl group cis to the 3-phenyl group. One of the main goals of this study was to compare the conformational and pharmacological behavior of these 2-methyl "beta-meperidine" analogues to their 2-desmethyl racemic counterparts (14a-c) previously reported in the literature. The 2-desmethyl and 2-methyl analogues were found to have very similar phenyl equatorial conformers as their lowest energy forms with the addition of a 2-methyl group diminishing conformational flexibility. The presence of the 2-methyl group appears to diminish affinity at the mu-receptor and also to somewhat diminish already weak antinociceptic agonist activity. Given the similarity in lowest energy conformation, this reduction is most likely caused by the unfavorable interaction of the methyl group itself with a local mu-receptor binding site. Superposition of the phenol OH and protonated amine nitrogen NH of either 2-methyl enantiomer of 13a in its lowest energy conformer with the same OH and NH groups of metazocine, used as a high affinity rigid analogue, leads to reasonable overlap. However, the N-substituents and the piperidine and phenyl rings do not overlap in this proposed pharmacophore, perhaps accounting for the rather poor affinities found for these 3-phenylpiperidines and the lack of N-substituent modulation of affinity and efficacy as in fused ring opioids.
    Journal of Medicinal Chemistry 11/1988; 31(10):2015-21. · 5.61 Impact Factor
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    ABSTRACT: 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.
    Molecular Pharmacology 10/1988; 34(3):363-76. · 4.41 Impact Factor
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    NIDA research monograph 02/1988; 90:144-51.
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    ABSTRACT: Four novel mu-selective peptide antagonists have been synthesized and examined for receptor binding, analgesic agonist and antagonist activity and energy conformational properties. These peptides were designed by analogy to results of molecular modeling of 3-phenyl piperidines which led to incorporating four modified tyrosine residues, m-Tyr, beta-methyl-m-Tyr, N-phenethyl-m-Tyr and alpha, beta-dimethyl-m-Tyr into D-Ala2-Met5-enkephalinamide. Peptides were synthesized by stepwise solution synthesis using an active ester coupling procedure. Receptor binding assays were performed on rat brain homogenates and data were analyzed by a modified version of the program LIGAND. Analgesic agonist and antagonist activity was evaluated by the mouse tail-flick test. Energy-optimized conformations were obtained using a program called Molecule-AIMS. The results demonstrate that relative ratios of in vivo agonist and antagonist potencies in D-Ala2-Met5-enkephalinamides can be modulated by chemical modification of the tyrosine residue. A shift in the phenolic-OH position from para to meta significantly enhances relative antagonist versus agonist activity; addition of a beta-CH3 group to the m-Tyr enhances mu-selectivity and leads to nearly equal agonist/antagonist activity. Energy conformational studies indicate that all analogs with high mu-receptor affinity examined have a common energy accessible B'II 2-3 turn conformation similar to that previously identified for high mu-affinity binding in peptides, lending further support to this candidate conformer. This conformer also has tyrosine side-chain angles which allowed total overlap with the amine and phenolic groups of a known structure of 3-(m-OH phenyl)-piperidine. This structural similarity together with the observation of mixed agonist antagonist activity in both types of opioids confirms the rationale upon which design of these peptides was based.
    International journal of peptide and protein research 10/1987; 30(3):299-317.
  • NIDA research monograph 02/1987; 76:309-15.
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    ABSTRACT: A series of 3-methyl-3-(m-hydroxyphenyl)piperidines with N-substituent variations have been synthesized and resolved, and an X-ray crystal structure of one analogue was determined. The compounds have been characterized, pharmacologically, by detailed opiate receptor binding studies and determination of in vivo analgesia and opiate antagonism. The results indicate that all compounds bind with high selectivity and moderate affinity to mu-receptors with no qualitative difference between enantiomeric pairs. By contrast a striking difference in activities is found, with the (-) enantiomers being pure agonists and the (+) enantiomers having both agonist and antagonist activity. The effect of N-substituents on relative agonist and antagonist potency does not mimic that of fused ring opiates with the N-phenethyl compound, the most potent antagonist. These results together with the X-ray structure obtained suggest that agonist and antagonist activity is initiated by a bimodel binding of the compounds in two different orientations at the mu-receptor site.
    Journal of Medicinal Chemistry 05/1986; 29(4):531-7. · 5.61 Impact Factor
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    G Frenking, G H Loew, J Lawson
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    ABSTRACT: The theoretically determined molecular structures of N-protonated 1,3,4,6 methyl-substituted 4-(m-OH phenyl) piperidines are correlated to their experimentally derived analgesic activities. It is concluded that the orientation of the 3-methyl group plays a crucial role in determining agonism and antagonism.
    NIDA research monograph 02/1986; 75:53-6.
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    ABSTRACT: A series of 4-(m-OH phenyl)-piperidine analogs with R4 = methyl or t-butyl and NR = methyl, allyl and phenethyl have been synthesized; and their receptor affinities, in vivo analgetic agonism and antagonism, and energy-conformational profiles determined. These analogs bind selectively and with moderate to high affinity to opioid mu-receptors. Binding in their preferred phenyl axial conformation appears to lead to meperidine-like agonism. In addition, for some R4 = methyl but not t-butyl compounds, binding of an energy-accessible phenyl equatorial conformation produces antagonism.
    NIDA research monograph 02/1986; 75:49-52.
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    NIDA research monograph 02/1986; 69:231-65.
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    ABSTRACT: The techniques of theoretical chemistry have been used to elucidate the molecular properties and modes of receptor binding that modulate receptor affinity and antagonist activity of the beta-carbolines, a class of potent benzodiazepine antagonists. Six analogs were chosen in order to investigate the role of the amine (NH) group, the aromatic nitrogen, and the C3-substituent in determining receptor affinities. Electrostatic potential mapping and characterization of explicit drug-receptor interactions have led to the hypothesis that simultaneous interaction of a model cationic arginine site with the N2 and C3-substituents could play a key role in determining receptor affinities. The electron-withdrawing effects of C3-substituents on the amine nitrogen appear less important, though interactions of these groups with an anionic glutamate or aspartate site could also occur at the receptor. Similarly, stacking interactions with neutral or cationic aromatic residues such as tryptophan or protonated histidine could occur, but do not appear to be determinants of the relative receptor affinity of the beta-carbolines.
    Molecular Pharmacology 08/1985; 28(1):17-31. · 4.41 Impact Factor
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    ABSTRACT: A number of beta-carboline analogs have been obtained or synthesized, and their in vitro receptor affinities and in vivo antagonist activities determined. The choice of analogs was made in order to explore the importance of the N9 -H, the aromatic nitrogen and the C3-ester moiety for high-receptor affinity and antagonist activity of this class of benzodiazepine antagonist. Among the analogs investigated, we describe the properties of 3-cyano-beta-carboline (1h), the first potent beta-carboline antagonist without a carbonyl at the C3-position. The results obtained indicate: (1) Specific interactions of the C3-substituent with key cationic receptor sites rather than electron-withdrawing properties are important for high-receptor affinity and antagonist activity. (2) Specific in-plane interactions of the aromatic nitrogen with a cationic receptor site, rather than stacking with neutral aromatic residues of the receptor are also important for high affinity and antagonist activity. (3) While the presence of an N9 -H enhances receptor affinity, interaction with an anionic receptor site does not appear essential for antagonist activity.
    Life Sciences 06/1984; 34(21):2007-13. · 2.56 Impact Factor
  • G Loew, L Toll, J Lawson, E Uyeno, H Kaegi
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    ABSTRACT: Pyrazolo[1,5-a]pyrimidines (PZP) have been reported to be specific anxiolytic agents which do not potentiate ethanol or barbiturates. To further investigate these compounds, three of the most promising analogs were synthesized and a tritium-labeled analog of one of them prepared by a new synthetic procedure. These analogs did not compete with [3H]flunitrazepam or [3H]beta-carboline ethyl ester binding nor did they potentiate the [3H]flunitrazepam binding. Receptor binding studies with the [3H]PZP revealed a low affinity receptor site, distinct from that of the benzodiazepines, but with only a small fraction (20%) of specific binding. Behavioral tests using three different animal models for anxiety: muricide, approach/avoidance conflict and two-chamber exploration tests gave conflicting results, positive in the first and negative in the latter two. Furthermore, these compounds were found not to be antagonists of diazepam's anticonvulsant activity. Taken together, these results, while provocative, do not support evidence that these analogs are promising specific anxiolytic agents.
    Pharmacology Biochemistry and Behavior 04/1984; 20(3):343-8. · 2.61 Impact Factor
    Life Sciences - LIFE SCI. 01/1984; 34(21):2007-2013.
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    ABSTRACT: A series of N-sec- and N-tert-alkylnormorphines was synthesized and evaluated for analgesic potency, antagonist activity, and opiate receptor binding. Computer-assisted conformational analysis profiles were utilized to assist in the selection of compounds for synthesis and correlation of receptor events with in vivo observations. N-tert-Alkylnormorphines 5a-c were devoid of agonist activity; however, some sec-alkyl analogues showed interesting mixed agonist-antagnoist actions. N-sec-Butyl- and N-(alpha-methylally)normorphine were separated into R and S isomers, which exhibited quantitative pharmacological differences. The N-sec-butyl S isomer 10a showed analgesia approximating morphine with nalorphine-like antagonist activity. Preliminary testing indicates only slight evidence for physical dependence with this compound.
    Journal of Medicinal Chemistry 06/1978; 21(5):415-22. · 5.61 Impact Factor
  • Proceedings of the Western Pharmacology Society 02/1978; 21:357-60.
  • Proceedings of the Western Pharmacology Society 02/1977; 20:467-71.
  • J A Lawson, J I DeGraw
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    ABSTRACT: The O-demethylation of codeine was effected by sodium propylmercaptide in dimethylformamide at 125 degrees C to afford morphine in 80% yield. Similar treatment of thebaine was unrewarding.
    Journal of Medicinal Chemistry 02/1977; 20(1):165-6. · 5.61 Impact Factor