Recent developments in cannabinoid ligands.

Over the past 40 years, much research has been carried out directed toward the characterization of the cannabinergic system. With the identification of two G-protein coupled receptors and the endogenous ligand, anandamide, pharmacological targets have expanded to encompass hydrolase and transport proteins as well as novel classes of cannabinoid ligands. Those ligands that demonstrate high affinity for the receptors and good biological efficacy are tied together through lipophilic regions repeatedly demonstrated necessary for activity. This review presents recent developments in the structure-activity relationships of several classes of cannabinoid ligands.

[1]  P. Little,et al.  Pharmacology and stereoselectivity of structurally novel cannabinoids in mice. , 1988, The Journal of pharmacology and experimental therapeutics.

[2]  H. Iwamura,et al.  In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor. , 2001, The Journal of pharmacology and experimental therapeutics.

[3]  R. Pertwee,et al.  Neuropharmacology and therapeutic potential of cannabinoids , 2000, Addiction biology.

[4]  G. Hynd,et al.  A pyridone analogue of traditional cannabinoids. A new class of selective ligands for the CB(2) receptor. , 2001, Bioorganic & medicinal chemistry.

[5]  J. Huffman,et al.  Cannabimimetic indoles, pyrroles and indenes. , 1999, Current medicinal chemistry.

[6]  C. Bass,et al.  SR-141716A-induced stimulation of locomotor activity A structure–activity relationship study , 2002, Pharmacology Biochemistry and Behavior.

[7]  A. Howlett,et al.  Structure-activity relationships for cannabinoid receptor-binding and analgesic activity: studies of bicyclic cannabinoid analogs. , 1993, Molecular pharmacology.

[8]  R. Razdan,et al.  Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor. , 2003, Molecular pharmacology.

[9]  P. Soubrié,et al.  Biochemical and pharmacological characterisation of SR141716A, the first potent and selective brain cannabinoid receptor antagonist. , 1995, Life sciences.

[10]  R. Pertwee,et al.  6"-Azidohex-2"-yne-cannabidiol: a potential neutral, competitive cannabinoid CB1 receptor antagonist. , 2004, European journal of pharmacology.

[11]  R. Mechoulam,et al.  Structure-activity relationships in the tetrahydrocannabinol series. Modifications on the aromatic ring and it the side-chain. , 1972, Arzneimittel-Forschung.

[12]  D. R. Compton,et al.  Structure-activity relationships of indole- and pyrrole-derived cannabinoids. , 1998, The Journal of pharmacology and experimental therapeutics.

[13]  Wei Li,et al.  Synthesis, biological evaluation, and structural studies on N1 and C5 substituted cycloalkyl analogues of the pyrazole class of CB1 and CB2 ligands. , 2004, Bioorganic & medicinal chemistry.

[14]  Herbert H Seltzman,et al.  Synthesis and Structure−Activity Relationships of Amide and Hydrazide Analogues of the Cannabinoid CB1 Receptor Antagonist N-(Piperidinyl)- 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716) , 2002 .

[15]  M. Herkenham,et al.  International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors , 2002, Pharmacological Reviews.

[16]  S. Mascarella,et al.  QSAR analysis of Delta(8)-THC analogues: relationship of side-chain conformation to cannabinoid receptor affinity and pharmacological potency. , 2000, Journal of medicinal chemistry.

[17]  Ming-Jung Wu,et al.  Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding. , 2000, Drug and alcohol dependence.

[18]  D. Gibson,et al.  Isolation and structure of a brain constituent that binds to the cannabinoid receptor. , 1992, Science.

[19]  Teresa Y. Phillips,et al.  Potent imidazole and triazole CB1 receptor antagonists related to SR141716. , 2004, Bioorganic & medicinal chemistry letters.

[20]  P. Soubrié,et al.  SR141716A, a potent and selective antagonist of the brain cannabinoid receptor , 1994, FEBS letters.

[21]  Hiromasa Hashimoto,et al.  4-Aryl/cycloalkyl-5-phenyloxazole derivatives as selective COX-2 inhibitors. , 2002, Bioorganic & medicinal chemistry letters.

[22]  A. Duranti,et al.  Synthesis and structure-activity relationships of a series of pyrrole cannabinoid receptor agonists. , 2003, Bioorganic & medicinal chemistry.

[23]  William J Welsh,et al.  Molecular interaction of the antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1- (2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide with the CB1 cannabinoid receptor. , 2002, Journal of medicinal chemistry.

[24]  A. Makriyannis,et al.  Structure-activity relationships of anandamide, an endogenous cannabinoid ligand. , 1999, Life sciences.

[25]  M. Grier,et al.  Novel pyrazole cannabinoids: insights into CB(1) receptor recognition and activation. , 2001, The Journal of pharmacology and experimental therapeutics.

[26]  P. Cowley,et al.  Recent advances in the cannabinoids , 2002 .

[27]  J. R. Wetzel,et al.  Antinociceptive (aminoalkyl)indoles. , 1991, Journal of medicinal chemistry.

[28]  A. Makriyannis,et al.  Pharmacophoric requirements for cannabinoid side chains: multiple bond and C1'-substituted delta 8-tetrahydrocannabinols. , 1998, Journal of medicinal chemistry.

[29]  John W. Huffman,et al.  Design, synthesis and pharmacology of cannabimimetic indoles , 1994 .

[30]  T. Bonner,et al.  A lysine residue of the cannabinoid receptor is critical for receptor recognition by several agonists but not WIN55212-2. , 1996, Molecular pharmacology.

[31]  M. Eissenstat,et al.  Morpholinoalkylindenes as antinociceptive agents: Novel cannabinoid receptor agonists , 1995 .

[32]  R. Pertwee.  Pharmacology of cannabinoid CB1 and CB2 receptors. , 1997, Pharmacology & therapeutics.

[33]  D. R. Compton,et al.  Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands. , 1996, The Journal of pharmacology and experimental therapeutics.

[34]  D. R. Compton,et al.  1-ALKYL-3-(1-NAPHTHOYL)PYRROLES : A NEW CLASS OF CANNABINOID , 1995 .

[35]  P. Casti,et al.  Synthesis and Characterization of NESS 0327: A Novel Putative Antagonist of the CB1 Cannabinoid Receptor , 2003, Journal of Pharmacology and Experimental Therapeutics.

[36]  R. Razdan,et al.  Resorcinol derivatives: a novel template for the development of cannabinoid CB(1)/CB(2) and CB(2)-selective agonists. , 2002, The Journal of pharmacology and experimental therapeutics.

[37]  B. Martin,et al.  Synthesis and pharmacology of a hybrid cannabinoid. , 2000, Bioorganic & medicinal chemistry.

[38]  A. Makriyannis,et al.  Molecular probes for the cannabinoid receptors. , 2000, Chemistry and physics of lipids.

[39]  M. Rinaldi-Carmona,et al.  The development of cannabinoid antagonists. , 1999, Current medicinal chemistry.

[40]  G. Bouchard,et al.  Exploration of the pharmacophore of 3-alkyl-5-arylimidazolidinediones as new CB1 cannabinoid receptor ligands and potential antagonists: Synthesis, lipophilicity, affinity, and molecular modeling : additions and corrections , 2002 .

[41]  A. Howlett,et al.  Nonclassical cannabinoid analgetics inhibit adenylate cyclase: development of a cannabinoid receptor model. , 1988, Molecular pharmacology.

[42]  S. Munro,et al.  Molecular characterization of a peripheral receptor for cannabinoids , 1993, Nature.

[43]  K. Rice,et al.  Cannabinoid structure-activity relationships: correlation of receptor binding and in vivo activities. , 1993, The Journal of pharmacology and experimental therapeutics.

[44]  Ming-Jung Wu,et al.  3-Indolyl-1-naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB(1) cannabinoid receptor. , 2003, Bioorganic & medicinal chemistry.

[45]  M. Krishnamurthy,et al.  Synthesis and testing of novel phenyl substituted side-chain analogues of classical cannabinoids. , 2003, Bioorganic & medicinal chemistry letters.

[46]  M. Tius,et al.  Enantiomeric resolution of a novel chiral cannabinoid receptor ligand. , 2002, Journal of biochemical and biophysical methods.

[47]  W. A. Hill,et al.  Classical/non-classical cannabinoid hybrids; stereochemical requirements for the southern hydroxyalkyl chain. , 1995, Life sciences.

[48]  S. Nikas,et al.  Novel 1′,1′-chain substituted Δ8-tetrahydrocannabinols , 2002 .

[49]  A. Howlett.  The CB1Cannabinoid Receptor in the Brain , 1998, Neurobiology of Disease.

[50]  Giovanni Loriga,et al.  Tricyclic pyrazoles. Part 1: synthesis and biological evaluation of novel 1,4-dihydroindeno[1,2-c]pyrazol-based ligands for CB1and CB2 cannabinoid receptors. , 2003, Bioorganic & medicinal chemistry.

[51]  S. Yu,et al.  3-(1',1'-Dimethylbutyl)-1-deoxy-delta8-THC and related compounds: synthesis of selective ligands for the CB2 receptor. , 1999, Bioorganic & medicinal chemistry.

[52]  T. Bonner,et al.  Structure of a cannabinoid receptor and functional expression of the cloned cDNA , 1990, Nature.

[53]  B. Thomas,et al.  Synthesis and pharmacological comparison of dimethylheptyl and pentyl analogs of anandamide. , 1997, Journal of medicinal chemistry.

[54]  P. Casellas,et al.  SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. , 1998, The Journal of pharmacology and experimental therapeutics.

[55]  F. Guarnieri,et al.  A critical role for a tyrosine residue in the cannabinoid receptors for ligand recognition. , 2002, Biochemical pharmacology.

[56]  R. Mechoulam,et al.  Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish , 1964 .

[57]  A. Makriyannis,et al.  Novel conformationally restricted tetracyclic analogs of delta8-tetrahydrocannabinol. , 1999, Bioorganic & medicinal chemistry letters.

[58]  H H Seltzman,et al.  Importance of the C-1 substituent in classical cannabinoids to CB2 receptor selectivity: synthesis and characterization of a series of O,2-propano-delta 8-tetrahydrocannabinol analogs. , 1997, Journal of medicinal chemistry.

[59]  W. Welsh,et al.  Derivation of a pharmacophore model for anandamide using constrained conformational searching and comparative molecular field analysis. , 1998, Journal of medicinal chemistry.

[60]  G. Gessa,et al.  Synthesis and biological evaluation of 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives as new ligands of cannabinoid receptors. , 2004, Bioorganic & medicinal chemistry.

[61]  B. Thomas,et al.  The bioactive conformation of aminoalkylindoles at the cannabinoid CB1 and CB2 receptors: insights gained from (E)- and (Z)-naphthylidene indenes. , 1998, Journal of medicinal chemistry.

[62]  D. R. Compton,et al.  A novel class of potent tetrahydrocannabinols (THCS): 2′-YNE-Δ8- and Δ9-THCS , 1995 .

[63]  D. R. Compton,et al.  Synthesis and pharmacology of a very potent cannabinoid lacking a phenolic hydroxyl with high affinity for the CB2 receptor. , 1996, Journal of medicinal chemistry.

[64]  J. Huffman,et al.  Synthesis of a tetracyclic, conformationally constrained analogue of Δ8-THC , 1998 .

[65]  S. Nikas,et al.  Pharmacophoric requirements for the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1'. , 2003, Journal of medicinal chemistry.

[66]  L. Gold,et al.  Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol. , 1992, The Journal of pharmacology and experimental therapeutics.

[67]  B. Thomas,et al.  Comparative receptor binding analyses of cannabinoid agonists and antagonists. , 1998, The Journal of pharmacology and experimental therapeutics.

[68]  J. Lange,et al.  Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB(1) cannabinoid receptor antagonists. , 2004, Journal of medicinal chemistry.

[69]  B. Martin.  Cellular effects of cannabinoids. , 1986, Pharmacological reviews.

[70]  R. Pertwee,et al.  (-)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens. , 2002, European Journal of Pharmacology.

[71]  A. Howlett,et al.  Determination and characterization of a cannabinoid receptor in rat brain. , 1988, Molecular pharmacology.

[72]  W. A. Hill,et al.  Unsaturated Side Chain β-11-Hydroxyhexahydrocannabinol Analogs , 1996 .

[73]  Wei Li,et al.  Synthesis and testing of novel classical cannabinoids: exploring the side chain ligand binding pocket of the CB1 and CB2 receptors. , 2003, Bioorganic & medicinal chemistry.