Biomedical subjects

Spyros P Nikas

Publications and source records attributed to Spyros P Nikas.

8 recordsLinked to original sources

PubMed2006

Mapping the melatonin receptor. 7. Subtype selective ligands based on beta-substituted N-acyl-5-methoxytryptamines and beta-substituted N-acyl-5-methoxy-1-methyltryptamines.

A series of beta-substituted and beta,beta-disubstituted N-acyl 5-methoxy-1-methyltryptamines and 5-methoxytryptamines have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was determined in a radioligand binding assay using cloned human MT(1) and MT(2) receptor subtypes expressed in NIH 3T3 cells. Agonist and antagonist potency of all analogues was measured using the pigment aggregation response of a clonal line of Xenopus laevis melanophores. beta-Methylmelatonin (17a) and beta,beta-dimethylmelatonin (17b), though showing a slight decrease in binding at human receptors, show an increase in potency on Xenopus. N-Butanoyl 5-methoxy-1-methyl-beta,beta-trimethylenetryptamine (12c) is an antagonist at human MT(1) receptors but an agonist at MT(2), while N-butanoyl 5-methoxy-1-methyl-beta,beta-tetramethylenetryptamine (13c) is an antagonist at MT(1) but had no action at MT(2) and is one of the first examples of an MT(1) selective antagonist.

Animals↗

PubMed2006

Methods for the synthesis of cannabinergic ligands.

During the last decade, numerous cannabinergic ligands with high affinity and selectivity profiles for cannabinoid receptors (CB1 and CB2) emerged from rigorously pursued structure-activity relationship studies. This chapter focuses on the synthetic aspects of key cannabinoid receptor probes representing the different classes of cannabinergic ligands that encompasses classical cannabinoids (CCs) including some covalent binding derivatives, nonclassical cannabinoids (NCCs), hybrid cannabinoids, aminoalkylindoles (AAIs), diarylpyrazoles, and the endocannabinoids.

Cannabinoids↗

PubMed2006

Cannabinoid receptors as therapeutic targets.

The cannabinoid receptors CB1 and CB2 are family A, G-protein Coupled Receptors that mediate the effects of cannabinoids, a class of compounds that are so named because the first members were isolates of the cannabis plant. In recent history, there has been much anecdotal evidence that the potent and diverse physiological responses produced by these compounds can be turned to therapeutic benefit for a wide variety of maladies. The remarkable abundance of cannabinoid receptors and the discovery of several endogenous ligands along with enzyme and transporter proteins for which they are substrates, suggests that an endogenous cannabinoid neuromodulatory system is an important mediator of biological function. For these reasons CB1 and CB2 receptors are attractive targets for the design of therapeutic ligands. The action of these receptors, however, may also be modulated by manipulating the enzymes and membrane transporters that regulate the endogenous ligands. Despite the range of physiological processes and activities that are mediated by cannabinoid receptors, it is clear that it is possible to produce ligands that result in differential responses. In this paper, we review the pharmacophoric elements that lead to these differential responses and in order to discuss them in context we present an overview of structural aspects governing cannabinoid receptor function, the cannabinergic system and its physiological functions.

Animals↗

PubMed2005

CB1 cannabinoid receptor ligands.

The CB1 receptor is expressed in the central nervous system and numerous other tissues including heart, lung and uterus and has been recognized as an important therapeutic target for pain, appetite modulation, glaucoma, multiple sclerosis and other indications. An interesting feature of this GPCR is its ability to be activated by a number of structurally different classes of compounds, thus, raising the possibility of multiple activated forms of the receptor. Understanding of the structure-activity relationships of cannabinergic ligands has paved the road for the development of novel ligands exhibiting receptor subtype selectivity and efficacy. This review highlights the important CB1 cannabinergic ligands developed to date.

Appetite Stimulants↗

PubMed2004

The role of halogen substitution in classical cannabinoids: a CB1 pharmacophore model.

The presence of halogens within the classical cannabinoid structure leads to large variations in the compounds' potencies and affinities for the CB1 receptors. To explore the structure activity relationships within this class of analogs we have used a series of halogen-substituted (-)-Delta8-tetrahydrocannabinol analogs and compared their affinities for the CB1 cannabinoid receptor. Our results indicate that halogen substitution at the end-carbon of the side chain leads to an enhancement in affinity with the bulkier halogens (Br, I) producing the largest effects. Conversely, 2-iodo substitution on the phenolic ring leads to a 2-fold reduction in affinity while iodo-substitution in the C1'-position of the side chain lowers the compound's affinity for CB1 by more than 8-fold. The pharmacophoric requirements resulting from halogen-substitution are explored using computer modeling methods.

Animals↗

PubMed2003

Conformational study of lipophilic ligands in phospholipid model membrane systems by solution NMR.

Phospholipid bicelles were employed as a membrane bilayer model in the conformational studies of two lipophilic cannabinoids, delta(8)-THC and its O-methyl ether analogue, Me-Delta(8)-THC using conventional high-resolution NMR. A preparation of 8% (w/v) phospholipid concentration and a high DMPC/DHPC ratio (q = 2.0) was found to be optimal for not only effectively incorporating our ligands, but also providing a more bilayerlike environment suitable for conformational studies. While the conformational differences between the two cannabinoids could not be observed in chloroform and were barely detectable in SDS micelle solution, there is an increasing preference for the pentyl tail of Delta(8)-THC to bend toward the tricyclic ring system with increasing proportions of DMPC in the bicelle preparation. Our results highlight the advantages of exploring the conformational properties of cannabinoids using bicelle preparations as a medium that more closely resembles biological membrane bilayers and eliminates the need for isotopic labeling. This approach should also be of more general value for studying the interactions of other cannabinoids and biologically active, hydrophobic or amphipathic, small molecules with membranes.

Chloroform↗

PubMed2003

Pharmacophoric requirements for the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1'.

Earlier work from our laboratories has provided evidence for the existence of a subsite within the CB1 and CB2 cannabinoid receptor binding domain corresponding to substituents at the benzylic side chain position of classical cannabinoids. The existence and stereochemical features of this subsite have now been probed through the synthesis of a novel series of (-)-Delta(8)-tetrahydrocannabinol analogues bearing C1'-ring substituents. Of the compounds described here, those with C1'-dithiolane (1c), C1'-dioxolane (2d), and cyclopentyl (2a) substituents exhibited the highest affinities for CB1 and CB2. We used molecular modeling approaches to better define the stereochemical limits of the putative subsite. In vitro pharmacological testing found 1c to be a potent CB1 agonist.

Animals↗

PubMed2002

Novel 1',1'-chain substituted Delta(8)-tetrahydrocannabinols.

1',1'-Cyclopropyl side chain substituents enhance the affinities of Delta(8)-tetrahydrocannabinol and respective cannabidiol analogues for the CB1 and CB2 cannabinoid receptors. The results support the hypothesis for a subsite within CB1 and CB2 binding domain at the level of the benzylic side chain carbon in the tetrahydrocannabinol and cannabidiol series. Efficient procedures for the synthesis of 1',1'-cyclopropyl analogues are described.

Analgesics, Non-Narcotic↗