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1.
ACS Chem Neurosci ; 15(11): 2160-2181, 2024 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-38766866

RESUMO

Synthetic cannabinoid receptor agonists (SCRAs) are a growing class of new psychoactive substances (NPS) commonly derived from an N-alkylated indole, indazole, or 7-azaindole scaffold. Diversification of this core (at the 3-position) with amide-linked pendant amino acid groups and modular N-alkylation (of the indole/indazole/7-azaindole core) ensures that novel SCRAs continue to enter the illicit drug market rapidly. In response to the large number of SCRAs that have been detected, pharmacological evaluation of this NPS class has become increasingly common. Adamantane-derived SCRAs have consistently appeared throughout the market since 2011, and as such, a systematic set of these derivatives was synthesized and pharmacologically evaluated. Deuterated and fluorinated adamantane derivatives were prepared to evaluate typical hydrogen bioisosteres, as well as evaluation of the newly detected AFUBIATA.


Assuntos
Agonistas de Receptores de Canabinoides , Halogenação , Indazóis , Indóis , Agonistas de Receptores de Canabinoides/farmacologia , Agonistas de Receptores de Canabinoides/química , Agonistas de Receptores de Canabinoides/síntese química , Relação Estrutura-Atividade , Animais , Indazóis/farmacologia , Indazóis/química , Indazóis/síntese química , Humanos , Indóis/farmacologia , Indóis/química , Adamantano/análogos & derivados , Adamantano/farmacologia , Adamantano/química , Deutério , Camundongos , Valina/análogos & derivados
2.
ChemMedChem ; : e202400163, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38782733

RESUMO

Despite their acknowledged significance in the inflammatory signalling cascade across a range of disease states, P2X7R antagonists have not yet proven to be effective in clinical trials. In this study, we present findings on P2X7 receptor antagonists that are based on a core adamantyl-cyanoguanidine-quinoline lead. To investigate the specific features of the cyanoguanidine moiety that influence compound potency we carried out a structure-activity relationship (SAR) study. Compound potency was assessed using an in vitro dye-uptake assay measuring P2X7R pore formation. While none of the compounds displayed superior potency to the lead, we established key structural requirements for potent P2X7R antagonism. An additional SAR using different aryl groups was performed based on the promising activity displayed by the squaramide derivative.

3.
Pharmacol Ther ; 237: 108228, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35716953

RESUMO

The purinoceptor 7 receptor (P2X7R) plays an important role in promoting inflammation in response to accumulating damage-associated molecular patterns (DAMPs) released from stressed or apoptotic cells and has been connected to various pathological conditions. The initial investment by large pharmaceutical companies such as AstraZeneca and Pfizer led to the development of several classes of P2X7R antagonists for the treatment of rheumatoid arthritis and Crohn's disease. While these compounds showed early promise as therapeutic agents and were found to potently inhibit adenosine triphosphate (ATP)-induced release of interleukin 1 beta (IL-1ß) in patient-derived monocytes primed with lipopolysaccharide (LPS), they failed to elicit a therapeutic benefit in phase II clinical trials. Within the last 10 years, a wealth of strong preclinical and clinical evidence has implicated IL-1ß as an aggressor in the development and progression of cardiovascular diseases, a cytokine modulated by the P2X7R. On account of the immune-mediated events that regulate atherosclerosis, antagonism of the P2X7R has been proposed as a therapeutic strategy due to the unique functionality of the receptor as an instigator of sterile inflammation. Here, we review the success and failures in P2X7R drug development to evaluate the major barriers to successful clinical translation of P2X7R antagonists. These avenues should be addressed by researchers and pharmaceutical companies to ensure future clinical success in the treatment of CAD.


Assuntos
Doença da Artéria Coronariana , Antagonistas do Receptor Purinérgico P2X , Trifosfato de Adenosina , Doença da Artéria Coronariana/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico , Lipopolissacarídeos , Preparações Farmacêuticas , Antagonistas do Receptor Purinérgico P2X/farmacologia , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Receptores Purinérgicos P2X7/uso terapêutico
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