Molecular Determinants for Cannabinoid Activity: Refinement of a Molecular Reactivity Template

Reggio, Patricia H.

doi:10.1037/e496672006-008

Cited by 2 publications

(3 citation statements)

References 17 publications

(21 reference statements)

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“…Although we cannot rule out a problem due to the shorter length of the Gln side chain, the complete loss of binding affinity with this residue points toward a requirement for positive charge. Based on traditional SAR and molecular modeling studies, the phenolic hydroxyl group at C-i of the !igand has been implicated in hydrogen bonding with the receptor (Reggio, 1987;Semus and Martin, 1990). In combination with mutational analysis (Song and Bonner, 1996), these studies suggested the possibility that Lys'92 acts as a hydrogen bond donor in an interaction with the oxygen of the phenolic hydroxyl.…”

Section: Discussionmentioning

confidence: 98%

“…Extensive SARs on classical and nonclassical cannabinoids and modeling studies have suggested that the phenolic hydroxyl is one of the key moieties conferring cannabimimetic activity (Razdan, 1986;Reggio, 1987;Semus and Martin, 1990). In contrast, a recent study using several cannabinoid analogues has indicated that a hydroxyl at the C-il position or the pyran oxygen in tricyclic cannabinoids may also be involved in hydrogen bonding with the receptor even in the absence of the phenolic hydroxyl group (Huffman et al, 1996).…”

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confidence: 99%

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Ligand Binding and Modulation of Cyclic AMP Levels Depend on the Chemical Nature of Residue 192 of the Human Cannabinoid Receptor 1

Chin

Lucas‐Lenard

Abadji

et al. 1998

Journal of Neurochemistry

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The human cannabinoid receptor associated with the CNS (CB1) binds Δ9‐tetrahydrocannabinol, the psychoactive component of marijuana, and other cannabimimetic compounds. This receptor is a member of the seven transmembrane domain G protein‐coupled receptor family and mediates its effects through inhibition of adenylyl cyclase. An understanding of the molecular mechanisms involved in ligand binding and receptor activation requires identification of the active site residues and their role. Lys192 of the third transmembrane domain of the receptor is noteworthy because it is the only nonconserved, charged residue in the transmembrane region. To investigate the properties of this residue, which are important for both ligand binding and receptor activation, we generated mutant receptors in which this amino acid was changed to either Arg (K192R), Gln (K192Q), or Glu (K192E). Wild‐type and mutant receptors were stably expressed in Chinese hamster ovary cells and were evaluated in binding assays with the bicyclic cannabinoid CP‐55,940 and the aminoalkylindole WIN 55,212‐2. We found that only the most conservative change of Lys to Arg allowed retention of binding affinity to CP‐55,940, whereas WIN 55,212‐2 bound to all of the mutant receptors in the same range as it bound the wild type. Analysis of the ligand‐induced inhibition of cyclic AMP production in cells expressing each of the receptors gave an EC50 value for each agonist that was comparable to its binding affinity, with one exception. Although the mutant K192E receptor displayed similar binding affinity as the wild type with WIN 55,212‐2, an order of magnitude difference was observed for the EC50 for cyclic AMP inhibition with this compound. The results of this study indicate that binding of CP‐55,940 is highly sensitive to the chemical nature of residue 192. In contrast, although this residue is not critical for WIN 55,212‐2 binding, the data suggest a role for Lys192 in WIN 55,212‐2‐induced receptor activation.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Ligand Binding and Modulation of Cyclic AMP Levels Depend on the Chemical Nature of Residue 192 of the Human Cannabinoid Receptor 1

Chin

Lucas‐Lenard

Abadji

et al. 1998

Journal of Neurochemistry

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“…Although previous molecular modeling studies support the existence of a pharmacophore that can accommodate classical and nonclassical cannabinoids − ,, as well as the aminoalkylindoles, , the ability to also include anandamide analogs had not been tested. Indeed, due to the anandamides' relatively unconstrained conformational freedom, the identification of a “relevant” alignment with fatty acid ethanolamides has proven to be particularly difficult.…”

Section: Discussionmentioning

confidence: 99%

Structure−Activity Analysis of Anandamide Analogs: Relationship to a Cannabinoid Pharmacophore

et al. 1996

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Anandamides are endogenous fatty acid ethanolamides that have been shown to bind to the cannabinoid receptor and possess cannabimimetic activity yet are structurally dissimilar from the classical cannabinoids found in Cannabis sativa. We have employed molecular dynamics studies of a variety of anandamides to characterize their conformational mobility and determine whether there are pharmacophoric similarities with delta 9-THC. We have found that a looped conformation of these arachidonyl compounds is energetically favorable and that a structural correlation between this low-energy conformation and the classical cannabinoids can be obtained with the superposition of (1) the oxygen of the carboxyamide with the pyran oxygen in delta 9-THC, (2) the hydroxyl group of the ethanol with the phenolic hydroxyl group of delta 9-THC, (3) the five terminal carbons and the pentyl side chain of delta9-THC, and (4) the polyolefin loop overlaying with the cannabinoid tricyclic ring. The shape similarity is extended to show that other fatty acid ethanolamides that possess varying degrees of unsaturation also vary in their conformational mobility, which affects their ability to overlay with delta 9-THC as described above. Within this series of compounds, the most potent analog, the tetraene (arachidonyl) analog (i.e., anandamide itself), was determined to have restricted conformational mobility that favored an optimal pharmacophore overlay with delta9-THC. Eight pharmacologically active anandamide analogs are shown to have similar conformational mobility and pharmacophore alignments that are conformationally accessible. Furthermore, when these compounds are aligned to delta 9-THC according to the proposed pharmacophore overlay, their potencies are predicted by a quantitative model of cannabinoid structure--activity relationships based solely on classical and nonclassical cannabinoids with a reasonable degree of accuracy. The ability to incorporate the pharmacological potency of these anandamides into the cannabinoid pharmacophore model is also shown to support the relevance of the proposed pharmacophore model.

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Molecular Determinants for Cannabinoid Activity: Refinement of a Molecular Reactivity Template

Cited by 2 publications

References 17 publications

Ligand Binding and Modulation of Cyclic AMP Levels Depend on the Chemical Nature of Residue 192 of the Human Cannabinoid Receptor 1

Ligand Binding and Modulation of Cyclic AMP Levels Depend on the Chemical Nature of Residue 192 of the Human Cannabinoid Receptor 1

Structure−Activity Analysis of Anandamide Analogs: Relationship to a Cannabinoid Pharmacophore

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