scholarly journals Biological Screening of a Large Combinatorial Library

1996 ◽  
Vol 1 (1) ◽  
pp. 27-31 ◽  
Author(s):  
Kenneth C. Appell ◽  
Thomas D. Y. Chung ◽  
Michael J. H. Ohlmeyer ◽  
Nolan H. Sigal ◽  
John J. Baldwin ◽  
...  
Keyword(s):  
Combinatorial Library ◽  
Solid Phase ◽  
Biological Activities ◽  
Synthesis Method ◽  
G Protein Coupled Receptors ◽  
Low Molecular Weight ◽  
Active Structures ◽  
Structure Activity ◽  
G Protein Coupled ◽  
Random Nature

Encoding technology has allowed for the creation of libraries of 50,000 or more low-molecular-weight compounds for biological testing. The current challenge is to properly and efficiently screen among these compounds for useful biological activities. In this example, actives against two related G-protein coupled receptors were sought from a combinatorial library of 56,000 members. The library was synthesized on solid phase using the split synthesis method and photochemically released for testing. At a screening concentration of 0.5-1 /LM, 86 unique structures were identified as active against one receptor and 24 were active against the other. Due to the random nature of compound sampling, five library equivalents or 280,000 beads were screened to ensure greater than 99% representation of library members. As a result, many actives appeared multiple times in the screen, verifying the encoding process. Further confirmation was obtained by resynthesis and testing of predicted active structures. A clear bias for specific "R" groups at each point of variation in the combinatorial library with little overlap between the two receptors has produced a clear structure-activity relationship on which to base further work.

Steroids as the novel class of high-affinity allosteric modulators of muscarinic receptors

2021 ◽  
Author(s):  
Eva Dolejší ◽  
Eszter Szánti-Pintér ◽  
Nikolai Chetverikov ◽  
Dominik Nelic ◽  
Alena Randáková ◽  
...  
Keyword(s):  
Muscarinic Receptors ◽  
Acetylcholine Receptors ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Allosteric Modulators ◽  
The Novel ◽  
Stress Control ◽  
Structure Activity ◽  
G Protein Coupled

Abstract The membrane cholesterol was found to bind and modulate the function of several G-protein coupled receptors including muscarinic acetylcholine receptors. We investigated the binding of 20 steroidal compounds including neurosteroids and steroid hormones to muscarinic receptors. Corticosterone, progesterone, and some neurosteroids bound to muscarinic receptors with an affinity of 100 nM or greater. We established a structure-activity relationship for steroid-based allosteric modulators of muscarinic receptors. Further, we show that corticosterone and progesterone allosterically modulate the functional response of muscarinic receptors to acetylcholine at physiologically relevant concentrations. It can play a role in stress control or in pregnancy, conditions where levels of these hormones dramatically oscillate. Allosteric modulation of muscarinic receptors via the cholesterol-binding site represents a new pharmacological approach at diseases associated with altered cholinergic signalling.

scholarly journals Mutagenesis Reveals Structure−Activity Parallels between Human A2AAdenosine Receptors and Biogenic Amine G Protein-Coupled Receptors

1997 ◽  
Vol 40 (16) ◽  
pp. 2588-2595 ◽  
Author(s):  
Qiaoling Jiang ◽  
Brian X. Lee ◽  
Marc Glashofer ◽  
A. Michiel van Rhee ◽  
Kenneth A. Jacobson
Keyword(s):  
G Protein ◽  
Biogenic Amine ◽  
G Protein Coupled Receptors ◽  
Structure Activity ◽  
G Protein Coupled

scholarly journals Oxytocin analogues with amide groups substituted by tetrazole groups in position 4, 5 or 9.

2007 ◽  
Vol 54 (4) ◽  
pp. 805-811 ◽  
Author(s):  
Michał Manturewicz ◽  
Zbigniew Grzonka ◽  
Lenka Borovicková ◽  
Jirina Slaninová
Keyword(s):  
Amino Acids ◽  
Solid Phase ◽  
Biological Activities ◽  
Synthesis Method ◽  
Oxytocin Receptor ◽  
Amide Group ◽  
Biologically Active ◽  
Side Chain ◽  
Electronic Effects

Eleven oxytocin analogues substituted in position 4, 5 or 9 by tetrazole analogues of amino acids were prepared using solid-phase peptide synthesis method and tested for rat uterotonic in vitro and pressor activities, as well as for their affinity to human oxytocin receptor. The tetrazolic group has been used as a bioisosteric substitution of carboxylic, ester or amide groups in structure-activity relationship studies of biologically active compounds. Replacement of the amide groups of Gln(4) and Asn(5) in oxytocin by tetrazole analogues of aspartic, glutamic and alpha-aminoadipic acids containing the tetrazole moiety in the side chains leads to analogues with decreased biological activities. Oxytocin analogues in which the glycine amide residue in position 9 was substituted by tetrazole analogues of glycine had diminished activities as well. The analysis of differences in rat uterotonic activity and in the affinity to human oxytocin receptors of analogues containing either an acidic 5-substituted tetrazolic group or a neutral 1,5- or 2,5-tetrazole nucleus makes it possible to draw some new conclusions concerning the role of the amide group of amino acids in positions 4, 5 and 9 of oxytocin for its activity. The data suggest that the interaction of the side chain of Gln(4) with the oxytocin receptor is influenced mainly by electronic effects and the hydrogen bonding capacity of the amide group. Steric effects of the side chain are minor. Substitution of Asn(5) by its tetrazole derivative gave an analogue of very low activity. The result suggests that in the interaction between the amide group of Asn(5) and the binding sites of oxytocic receptor hydrogen bonds are of less importance than the spatial requirements for this group.

scholarly journals IL-10 Enhances CCL2 Release and Chemotaxis Induced by CCL16 in Human Monocytes

2005 ◽  
Vol 18 (2) ◽  
pp. 339-349 ◽  
Author(s):  
T. Musso ◽  
P. Cappello ◽  
S. Stornello ◽  
D. Ravarino ◽  
C. Caorsi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Proinflammatory Cytokines ◽  
Pertussis Toxin ◽  
Biological Activities ◽  
G Protein Coupled Receptors ◽  
Chemotactic Response ◽  
Human Monocytes ◽  
Activated Monocytes ◽  
G Protein Coupled ◽  
Ccl2 Production

CCL16 is a CC chemokine originally identified as a liver-expressed chemokine. Its expression has been detected in activated monocytes where it is up-regulated by stimulation with IL-10. This is in contrast with IL-10's inhibition of the expression of most chemokines. CCL16 is chemotactic for monocytes, lymphocyte and dendritic cells. We investigated whether CCL16 displays biological activities other than chemotaxis and whether IL-10 affects monocyte response to CCL16. We show that CCL16 induces the expression of CCL2 at the mRNA and protein level, but does not affect that of CCL5, CCL18 and proinflammatory cytokines. This effect was prevented by treatment with pertussis toxin and may thus be mediated by G-protein-coupled receptors. IL-10 markedly increased CCL2 production induced by CCL16, but suppressed that of CXCL8. It also enhanced the chemotactic response to CCL16. Addition of antibodies blocking CCR1, but not CCR8, prevented this enhanced chemotactic response and suggested that CCR1 is primarily involved. We propose that IL-10 modulates the effects of CCL16 on monocytes by increasing their CCR1-dependent response. The coordinated secretion of CCL16 and IL-10 may thus enhance monocyte infiltration.

scholarly journals A Multisite Model of Allosterism for the Adenosine A1 Receptor

2020 ◽  
Author(s):  
Giuseppe Deganutti ◽  
Kerry Barkan ◽  
Graham Ladds ◽  
Christopher A Reynolds
Keyword(s):  
G Protein Coupled Receptors ◽  
Receptor Subtype ◽  
Allosteric Modulators ◽  
Allosteric Site ◽  
Structure Activity ◽  
Central Nervous Systems ◽  
A1 Receptor ◽  
Approved Drugs ◽  
G Protein Coupled ◽  
Target Side

ABSTRACTDespite being a target for about one-third of approved drugs, G protein-coupled receptors (GPCRs) still represent a tremendous reservoir for therapeutic strategies against countless diseases. For example, several cardiovascular and central nervous systems conditions could benefit from clinical agents that activate the adenosine 1 receptor (A1R), however, the pursuit of A1R agonists for clinical use are usually impeded by both on- and off-target side effects. One of the possible strategies to overcome this issue is the development of positive allosteric modulators (PAMs) capable of selectively enhancing the effect of a specific receptor subtype and triggering functional selectivity (a phenomenon also referred to as bias). Intriguingly, besides enforcing the effect of agonists upon binding to an allosteric site, most of the A1R PAMs display intrinsic partial agonism and orthosteric competition with antagonists. To rationalize this behaviour, we simulated the binding of the prototypical PAMs PD81723 and VCP171, the antagonist 13B, and the bitopic agonist VCP746. We propose that a single PAM can bind several A1R sites rather than a unique allosteric pocket, reconciling the structure-activity relationship and the mutagenesis results.

Structure-Activity Relationships of G Protein-Coupled Receptors

1999 ◽  
Vol 30 (6) ◽  
pp. 420-435 ◽  
Author(s):  
Alfredo Ulloa-Aguirre ◽  
Dinesh Stanislaus ◽  
Jo Ann Janovick ◽  
P.Michael Conn
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
G Protein Coupled
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