Synthesis and Analgesic Activity of New α-Pinene-Based Cineol-Like Methanopyrano[4,3-b]pyrans

A large series of new chiral heterocyclic cineol-like methanopyrano[4,3-b]pyrans was prepared by reactions of the (+)- and (–)-isomers of 8-hydroxy-6-hydroxymethyllimonene, obtained from the corresponding α-pinenes with high optical purity, and aromatic aldehydes with OH and/or OMe substituents. The synthesized heterocycles were tested for analgesic activity in the in vivo tests. Some of cineol-like methanopyrano[4,3-b]pyrans synthesized from 4-methoxybenzaldehyde, 2,3,4-trimethoxybenzaldehyde and 2,4,5-trimethoxybenzaldehyde exhibit significant analgesic activity. Experiments in vivo with agonists and antagonists of several neurotransmitter systems helped to elucidate the probable mechanism of analgesic action mediated by these compounds. Thus, cannabinoid CB1 receptors do not appear to be involved in the development of the analgesic effect. Opioid and GABAA receptors of the central nervous system likely play a significant role in the analgesic activity of the tested cineol-like methanopyrano[4,3-b]pyrans. (3R,4aR,5R,8S,8aS)-5-(4-Methoxyphenyl)-2,2,8a-trimethylhexahydro-2H,5H-3,8-methanopyrano[4,3-b]pyran likely mediates its analgesic effect through both muscarinic and adrenergic receptors of the central nervous system. Serotonin receptors may be involved into the mechanism of analgesic action of (3R,4aR,5R,8S,8aS)-5-(2,3,4-trimethoxyphenyl)-2,2,8a-trimethylhexahydro-2H,5H-3,8-methanopyrano[4,3-b]pyran and (3R,4aR,5R,8S,8aS)-5-(2,4,5-trimethoxyphenyl)-2,2,8a-trimethylhexahydro-2H,5H-3,8-methanopyrano[4,3-b]pyran.