Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During a search for novel drugs possessing analgesic properties but devoid of the psychotropic effects of marijuana, a group of molecules designated as nonclassical cannabinoids was synthesized by Pfizer. Of these nonclassical cannabinoids CP-55,940 has received the most attention principally because it was used as the high affinity radioligand during the discovery and characterization of the G-protein-coupled cannabinoid receptor. In an effort to obtain information on the stereoelectronic requirements at the cannabinoid receptor active site, we have studied the conformational properties of CP-55,940 using a combination of solution NMR and computer modeling methods. Our data show that for the most energetically favored conformation, (i) the aromatic phenol ring is perpendicular to the cyclohexane ring, and the phenolic O-H bond is coplanar with the aromatic ring and points away from the cyclohexyl ring; ii) the dimethylheptyl chain adopts one of four preferred conformations in all of which the chain is almost perpendicular to the phenol ring; and iii) an intramolecular H-bond between the phenolic and hydroxypropyl groups allows all three hydroxyl groups of CP-55,940 to be oriented toward the upper face of the molecule. Such an orientation by the OH groups may be a characteristic requirement for cannabimimetic activity.
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PMID:The conformational properties of the highly selective cannabinoid receptor ligand CP-55,940. 863 69

Presynaptic imidazoline receptors (IRs) which inhibit norepinephrine (NE) release from sympathetic nerve endings have been identified in cardiovascular tissue of man, rabbit, rat, and guinea pig. They do not belong to one of the classical presynaptic inhibitory receptor classes such as alpha 2-adrenoceptors or H3 histamine receptors, and there is also no relation to I1- and I2-imidazoline binding sites. Segments of human right atrial appendages preincubated with [3H]NE were used to determine unknown pharmacologic properties of the presynaptic IRs. In the presence of 1 microM rauwolscine, S23230, the (-)-enantiomer of the racemic oxazoline derivative S22687 (5-(2(methyl-phenoxy-methyl)-1,3-oxazoline-2-yl)amine) exhibited low potency in inhibiting the electrically evoked [3H]NE release (pIC30% = 4.96), whereas the (+)-enantiomer S23229 and the racemate S22687 were ineffective. The IR-mediated inhibitory effect of the imidazoline BDF 6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline) and the guanidine aganodine on evoked [3H]NE release from sympathetic nerves in human atrial appendages was counteracted by rauwolscine (with very low potency) and by the cannabinoid CB1-receptor antagonist SR141715A (N-[piperdin-1-yl]-5-[4-chlorophenyl]-2,4-dichlorophenyl]-4- methyl-1H-pyrazole-3-carboxamide). The inhibitory effect of moxonidine on evoked [3H]NE release (which is exclusively mediated via activation of alpha 2-autoreceptors) was antagonized with high potency by rauwolscine, but not by SR141716A. The cannabinoid CB1 receptor agonists CP55,940([(-)-Cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl] -trans-4- (3-hydroxy-propyl)cyclohexane]) and anandamide inhibited evoked [3H]NE release. Inhibition by CP55,940 and anandamide was abolished by 1 microM SR141716A as well as by 30 microM rauwolscine. In radioligand binding experiments on membranes from human atrial appendages (alpha 2- and sigma-binding sites were masked), cannabinoid receptor ligands and IR agonists displaced the radiolabeled guanidine derivative [3H]DTG (1,3-di-o-tolyguanidine, an agonist at presynaptic IRs) from its binding sites. Comparison of the potencies of these drugs determined in the competition experiments with [3H]DTG with those in inhibiting NE release via activation of the presynaptic IRs in the same tissue revealed a correlation. The present results suggest, e.g., that the presynaptic IRs may have certain binding domains in common with presynaptic cannabinoid receptors or that both receptors are different proteins which interact with each other in an unknown manner.
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PMID:Presynaptic imidazoline receptors. New developments in characterization and classification. 1041 12