Latest developments in small molecule analgesics: heterocyclic scaffolds I

In these review series, recent reports on the design and development of analgesic molecules were reviewed. The primary aim is to examine heterocyclic frameworks involved in pain modulation and, where applicable, to establish structure - activity relationships (SARs). Currently, nine major pathways have been described for pain relief, including prostaglandin synthesis inhibition, opioid receptor modulation, sodium channel blockade, enhancement of serotonin and norepinephrine levels, cannabinoid receptor (CBR) binding, N-methyl-D-aspartate (NMDA) receptor antagonism, transient receptor potential cation channel subfamily V member 1 (TRPV1) antagonism, and P2X purinergic receptor blockade. After reviewing literature, owing to extensive research in this field, the study was divided into two separate parts, azoles and non-azoles. In this first study, the molecules exhibiting analgesic activity containing azole-based rings such as pyrrole, pyrazole, indole, imidazole, benzimidazole, indazole, triazole, tetrazole, (benz)oxazole, thiazole, benzothiazole, oxadiazole, and thiadiazole were comprehensively reviewed. These ring systems were classified in the whole study, first according to their molecular weights and then by bioisosteric similarity. Accordingly, this review also provides a framework for the compounds incorporating these core structures in the design of novel molecules with potential analgesic properties. In conclusion, these works highlight the current progress and emerging strategies in analgesic drug discovery and development.