Analgesics, QSAR

Cruz-Monteagudo M, Borges F, Cordeiro MN (2008) Desirability-based multiobjective optimization for global QSAR studies application to the design of novel NSAIDs with improved analgesic, antiinflammatory, and ulcerogenic profiles. J Comput Chem 29(14) 2445-2459... 

Complete removal of the 4-phenyl substituent of the reversed ester of pethidine results in a drastic fall in potency as judged from tests in mice (see 23, R = Et). However, certain esters of l-methyl-4-piperidinol formed from aromatic acids display antinociceptive activities in the morphine to codeine range of potency (23).<68) A QSAR study of such esters has been made and a substitution pattern of the phenyl group defined for optimal activity/69 The relevance of these compounds to morphine-type analgesics is doubtful since the more active members show marginal or no affinity for opioid receptors of rat brain homogenates and display no physical dependence in monkeys. 

A QSAR study(50) of the series 13-15 showed that their analgesic action was positively dependent on the lipophilicity and molecular mass of the N-substituent but negatively dependent on the lipid affinity of the 4-substituent additional to the anilido function. A Chinese group has studied a variety of cis-3 - methylfentanyl derivatives with modified N-phenethyl substituents. Some of the compounds approached the potency of the parent and one exceeded it (see 18).(51) All compounds had high lipid solubilities as judged... 

Broto, P, Moreau, G. and Vandycke, C. (1984c). Molecular Structures Perception, Autocorrelation Descriptor and SAR Studies. Use of the Autocorrelation Descriptors in the QSAR Study of Two Non-Narcotic Analgesic Series. Eur.J.Med.Chem., 19,79-84. 

Recently, Keimowitz et al [38], aware that the cannabinoid side chain is a key pharmacophore, studied a series of 36 side-chain substituted A8-THCs with a wide range of pharmacological potency using computational molecular modelling and QSAR analysis. They showed that for optimum affinity and potency, the side chain must have conformational freedom that allows its terminus to fold back and come into proximity with the phenolic ring. In vivo THC is oxidized to the more potent ll-OH-A9-THC. Modifications of this structure yield 9-nor-9P-OH-hexahydrocannobinol (HHC) that has exhibited enhanced analgesic activity. 

Deeb O. and Drabh M,(2010). Exploring QSARs of some analgesic compounds by PC-... 

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