Cannabinoid receptors and their ligands

There are at least two types of cannabinoid receptors, CB(1) and CB(2), both coupled to G proteins. CB(1) receptors exist primarily on central and peripheral neurons, one of their functions being to modulate neurotransmitter release. CB(2) receptors are present mainly on immune cells. Their roles are proving more difficult to establish but seem to include the modulation of cytokine release. Endogenous agonists for cannabinoid receptors (endocannabinoids) have also been discovered, the most important being arachidonoyl ethanolamide (anandamide), 2-arachidonoyl glycerol and 2-arachidonyl glyceryl ether. Other endocannabinoids and cannabinoid receptor types may also exist. Although anandamide can act through CB(1) and CB(2) receptors, it is also a vanilloid receptor agonist and some of its metabolites may possess yet other important modes of action. The discovery of the system of cannabinoid receptors and endocannabinoids that constitutes the "endocannabinoid system" has prompted the development of CB(1)- and CB(2)-selective agonists and antagonists/inverse agonists. CB(1)/CB(2) agonists are already used clinically, as anti-emetics or to stimulate appetite. Potential therapeutic uses of cannabinoid receptor agonists include the management of multiple sclerosis/spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, vasodilation that accompanies advanced cirrhosis, and cancer. Following their release onto cannabinoid receptors, endocannabinoids are removed from the extracellular space by membrane transport and then degraded by intracellular enzymic hydrolysis. Inhibitors of both these processes have been developed. Such inhibitors have therapeutic potential as animal data suggest that released endocannabinoids mediate reductions both in inflammatory pain and in the spasticity and tremor of multiple sclerosis. So too have CB(1) receptor antagonists, for example for the suppression of appetite and the management of cognitive dysfunction or schizophrenia.     

Cannabinoid receptors and their endogenous ligands

Delta9-Tetrahydrocannabinol, a major psychoactive component of marijuana, has been shown to interact with specific cannabinoid receptors, thereby eliciting a variety of pharmacological responses in experimental animals and human. In 1990, the gene encoding a cannabinoid receptor (CB1) was cloned. This prompted the search for endogenous ligands. In 1992, N-arachidonoylethanolamine (anandamide) was isolated from pig brain as an endogenous ligand, and in 1995, 2-arachidonoylglycerol was isolated from rat brain and canine gut as another endogenous ligand. Both anandamide and 2-arachidonoylglycerol exhibit various cannabimimetic activities. The results of structure-activity relationship experiments, however, revealed that 2-arachidonoylglycerol, but not anandamide, is the intrinsic natural ligand for the cannabinoid receptor. 2-Arachidonoylglycerol is a degradation product of inositol phospholipids that links the function of cannabinoid receptors with the enhanced inositol phospholipid turnover in stimulated tissues and cells. The possible physiological roles of cannabinoid receptors and 2-arachidonoylglycerol in various mammalian tissues such as those of the nervous system are discussed.     

ErbB receptors and their ligands in the breast

ErbB receptor tyrosine kinases are membrane-bound receptors that possess intrinsic, ligand-activated, tyrosine kinase activity. Binding of growth factors to these receptors induces the formation of ErbB homo- and heterodimers and initiates a signalling cascade that traverses the cytoplasm to communicate with the nucleus and the cytoskeleton. The effect of this cascade is the regulation of cellular proliferation, differentiation, apoptosis, migration and adhesion. Although ErbB signalling is important for normal growth and development in the breast, a dysregulation of ErbB activity can lead to tumourigenesis. This review will focus on the role of ErbB signalling in both normal mammary gland development and breast cancer, with an emphasis on the mechanisms behind receptor activation and the therapeutic agents designed to inhibit ErbB activity.     

The Wellcome Foundation lecture, 1982. Opioid peptides and their receptors

The remarkable feature of the opioid system is the complexity of its ligands and their interactions with the mu-, delta- and kappa-binding sites. The three endogenous opioid precursors give rise to more than ten opioid fragments. The fragments of pro-opiocortin and pro-enkephalin have affinities mainly to the mu- and delta-binding sites and those of pro-dynorphin have a preference for the kappa-binding site. It is important to realize that some of the larger fragments may have pharmacological actions that are of a non-opioid character. As the endogenous opioid peptides bind to more than one of the types of binding sites, it was necessary to obtain synthetic compounds that bind almost exclusively at one site. There are now agonists for which this aim has been achieved but we still require antagonists that are exclusively selective for only one opioid site. The results obtained with opioid peptides or non-peptides having such qualities would be the physiological basis for a correlation of the binding at mu-, delta- and kappa-receptors with their pharmacological effects. Furthermore, since almost all endogenous opioid ligands are degraded by peptidases, it is necessary to synthesize non-toxic inhibitors of those peptidases that play a role in opioid transmission. Related to this problem is the need to develop methods for the study of the release of various endogenous opioid peptides under physiological conditions.     

A new approach for quantitation of receptors and their ligands

A novel and sensitive method for quantitating receptors and their ligands is described, using the calf uterine estrogen receptor and estradiol as a model system. When ligand conjugated to malate dehydrogenase is incubated with the estrogen receptor, the enzyme is inhibited proportionately to the concentration of receptor. However, receptor saturated with free ligand has almost no effect on the ligand-conjugated enzyme. The assay can detect as little as three femtomoles of receptor and one femtomole of estradiol and can, in principle, be applied to any receptor-ligand interaction.     

Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling

Angiopoietins are ligands of the Tie2 receptor that control angiogenic remodeling in a context-dependent manner. Tie signaling is involved in multiple steps of the angiogenic remodeling process during development, including destabilization of existing vessels, endothelial cell migration, tube formation and the subsequent stabilization of newly formed tubes by mesenchymal cells. Beyond this critical role in blood vessel development, recent studies suggest a wider role for Tie2 and angiopoietins in lymphangiogenesis and the development of the hematopoietic system, as well as a possible role in the regulation of certain non-endothelial cells. The outcome of Tie signaling depends on which vascular bed is involved, and crosstalk between different VEGFs has an important modulating effect on the properties of the angiopoietins. Signaling through the Tie1 receptor is not well understood, but Tie1 may have both angiopoietin-dependent and ligand-independent functions. Changes in the expression of Tie receptors and angiopoietins occur in many pathological conditions, and mutations in the Tie2 gene are found in familial cases of vascular disease.     

Eph receptors and their ephrin ligands are expressed in developing mouse pancreas

Pancreas development involves branching morphogenesis concomitantly to differentiation of endocrine, exocrine and ductal cell types from a single population of pancreatic precursors. These processes depend on many signals and factors that also control development of the central nervous system. In the latter, Eph receptors and their class-A (GPI-anchored) and class-B (transmembrane) ephrin ligands control cell migration and axon-pathfinding, help establish regional patterns and act as labels for cell positioning. This raised the question as to whether and where Ephs and ephrins are expressed during pancreas development. Here we have identified the Eph and ephrin genes that are expressed in mouse embryonic pancreas, as detected by RT-PCR analysis. In situ hybridization experiments showed that Ephs and ephrins are mainly expressed in the burgeoning structures of the epithelium which differentiate into exocrine acini. Binding experiments on whole pancreas demonstrated the presence of functional Eph receptors. They showed that EphBs are expressed by the pancreatic epithelium at embryonic day (e) 12.5 and that, from e14.5 on, Ephs of both classes are expressed by the pancreatic epithelium and then become restricted to developing acini. We conclude that specific members of the Eph/ephrin family are expressed in embryonic pancreas according to a dynamic temporal and regional pattern.     

Opioid agonist and antagonist bivalent ligands as receptor probes

Bivalent ligands are molecules which contain two pharmacophores linked by a connecting chain (spanner). The present report describes the use of oxymorphamine (Oxy) and naltrexamine (Nal) as the opioid agonist and antagonist pharmacophores separated by a variable length spanner composed of succinyl-bis-oligoglycine. The agonist series, [CH2CO(Gly)nOxy]2, and antagonist series, [CH2CO(Gly)nNal]2, were synthesized (n = 0-4) and tested on the electrically stimulated GPI. All of the antagonist bivalent ligands (Nal) antagonized the effects of morphine, with the greatest potency enhancement (60 x) residing with the succinyl (n = 0) congener. A dramatically different SAR profile was observed in the agonist (Oxy) series where the greatest potency enhancement (17 x) occurs when n = 2. By contrast with the antagonist series the agonist bivalent ligand with n = 0 is equipotent to its monovalent agonist analogue. The significance of these results with respect to the possibility of discrete opioid agonist and antagonist recognition sites are discussed.     

Class II cytokine receptors and their ligands: key antiviral and inflammatory modulators

Class II cytokine receptors were originally defined on the basis of sequence homologies in the extracellular domains of receptors for interferons (IFNs) and interleukin-10 (IL-10), and the ligands, known as class II cytokines, also have a common structure. More recently, a series of new receptors and cytokines that belong to this family have been discovered. The therapeutic potential of the 'old' members of this family, IFNs and IL-1, is recognized in the clinic, and the existence of structurally related molecules is raising expectations for additional clinical applications. In this review, I discuss both structural and biological data that are emerging about this family of receptors and ligands, to highlight the potential applications of modulating the activity of these cytokines.     

1,2,5-Thiadiazole derivatives are potent and selective ligands at human 5-HT1A receptors

Amino acid derivatives of 1,2,5-thiadiazol-3-yl-piperazine related to (+)-WAY-100135 and WAY-100635 are potent 5-HT1A receptor agonists and antagonists, which have selective affinity for 5-HT1A receptors versus alpha1 and dopamine (D2, D3, and D4) receptors.     

Nootropic and anxiolytic properties of endogenous ligands of benzodiazepine receptors and their structural analogs

Experiments on mice and rats were made to study the nootropic and anxiolytic properties of endogenous ligands of benzodiazepine receptors of nicotinamide and inosin and of their new structural analogs--NMF and AZN. They were shown to have overt antihypoxic and anxiolytic effects. NMF and AZN given in 10-fold lower doses than endogenous benzodiazepine ligands appeared more active than these compounds and almost similar to diazepam as regards the activity. The data obtained point to the possibility of a purposeful search for new efficacious psychotropic and nootropic substances in the series of compounds structurally related to endogenous ligand of benzodiazepine receptors.