Latest developments in small molecule analgesics: heterocyclic scaffolds II

In this review, the primary aim is to examine non-azole ring systems that have analgesic activity and, where applicable, to establish structure - activity relationships (SARs) with the nine major pathways, 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, have been described for pain relief. Analgesic effects have been observed in compounds containing ring systems such as piperidine, piperazine, pyridine, pyridazine, pyrazine, morpholine, thiomorpholine, pyran, thiopyran, indane, benzofuran, benzothiophene, quinoline, quinazoline, and chromene. These ring systems were classified in the whole study, first according to their molecular weights and then by bioisosteric similarity as same as first part. Differing from the initial study of this work, the advantages of newly developed and approved drug formulations were evaluated, and recent advances in analgesic drug development were discussed. Accordingly, this review also provides a framework for the formulation of 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.