N-acyl-dopamines: novel synthetic CB 1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo
Tiziana Bisogno,Dominique Melck,Bobrov MYu,Natalia Gretskaya,Vladimir V. Bezuglov,L. De Petrocellis,V. Di Marzo +6 more
TLDR
It is concluded that NADAs, and AA-DA in particular, may be novel and useful probes for the study of the ECS.Abstract:
We reported previously that synthetic amides of polyunsaturated fatty acids with bioactive amines can result in substances that interact with proteins of the endogenous cannabinoid system (ECS). Here we synthesized a series of N-acyl-dopamines (NADAs) and studied their effects on the anandamide membrane transporter, the anandamide amidohydrolase (fatty acid amide hydrolase, FAAH) and the two cannabinoid receptor subtypes, CB(1) and CB(2). NADAs competitively inhibited FAAH from N18TG2 cells (IC(50)=19-100 microM), as well as the binding of the selective CB(1) receptor ligand, [(3)H]SR141716A, to rat brain membranes (K(i)=250-3900 nM). The arachidonoyl (20:4 omega 6), eicosapentaenoyl (20:5 omega 3), docosapentaenoyl (22:5 omega 3), alpha-linolenoyl (18:3 omega 3) and pinolenoyl (5c,9c,12c 18:3 omega 6) homologues were also found to inhibit the anandamide membrane transporter in RBL-2H3 basophilic leukaemia and C6 glioma cells (IC(50)=17.5-33 microM). NADAs did not inhibit the binding of the CB(1)/CB(2) receptor ligand, [(3)H]WIN55,212-2, to rat spleen membranes (K(i)>10 microM). N-arachidonyl-dopamine (AA-DA) exhibited 40-fold selectivity for CB(1) (K(i)=250 nM) over CB(2) receptors, and N-docosapentaenoyl-dopamine exhibited 4-fold selectivity for the anandamide transporter over FAAH. AA-DA (0.1-10 microM) did not displace D1 and D2 dopamine-receptor high-affinity ligands from rat brain membranes, thus suggesting that this compound has little affinity for these receptors. AA-DA was more potent and efficacious than anandamide as a CB(1) agonist, as assessed by measuring the stimulatory effect on intracellular Ca(2+) mobilization in undifferentiated N18TG2 neuroblastoma cells. This effect of AA-DA was counteracted by the CB(1) antagonist SR141716A. AA-DA behaved as a CB(1) agonist in vivo by inducing hypothermia, hypo-locomotion, catalepsy and analgesia in mice (1-10 mg/kg). Finally, AA-DA potently inhibited (IC(50)=0.25 microM) the proliferation of human breast MCF-7 cancer cells, thus behaving like other CB(1) agonists. Also this effect was counteracted by SR141716A but not by the D2 antagonist haloperidol. We conclude that NADAs, and AA-DA in particular, may be novel and useful probes for the study of the ECS.read more
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The Endocannabinoid System as an Emerging Target of Pharmacotherapy
TL;DR: A comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy is provided.
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Role of Endogenous Cannabinoids in Synaptic Signaling
TL;DR: The synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation, and the fine-grain anatomical distribution of the neuronal cannabinoid receptor CB1 is described in most brain areas, emphasizing its general presynaptic localization and role in controlling neurotransmitter release.
Journal ArticleDOI
International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2
Roger G. Pertwee,Allyn C. Howlett,Mary E. Abood,Stephen P.H. Alexander,V. Di Marzo,Maurice R. Elphick,Peter J. Greasley,Harald S. Hansen,George Kunos,Ken Mackie,Raphael Mechoulam,Ruth Alexandra Ross +11 more
TL;DR: This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non- CB1, non-CB2 established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors.
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Endocannabinoid-Mediated Control of Synaptic Transmission
TL;DR: This review aims to integrate the current understanding of functions of the endocannabinoid system, especially focusing on the control of synaptic transmission in the brain, and summarizes recent electrophysiological studies carried out on synapses of various brain regions and discusses how synaptic transmission is regulated by endoc cannabinoidoid signaling.
Journal ArticleDOI
An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors
Susan M. Huang,Tiziana Bisogno,Marcello Trevisani,Abdulmonem Al-Hayani,Luciano De Petrocellis,Filomena Fezza,Michele Tognetto,Timothy J. Petros,Jocelyn F. Krey,Constance J. Chu,Jeffrey D. Miller,Stephen N. Davies,Pierangelo Geppetti,J. Michael Walker,Vincenzo Di Marzo +14 more
TL;DR: The hypothesis, based on previous structure-activity relationship studies and the availability of biosynthetic precursors, that N-arachidonoyl-dopamine (NADA) is an endogenous “capsaicin-like” substance in mammalian nervous tissues is examined and found that NADA occurs in nervous tissues.
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