Ligand-receptor interactions stereoselectivity

A further problem was the presumed lack of, or at least a low degree of, stereospecificity of cannabinoid action. As all receptors are asymmetric, it is conceivable that their interactions with asymmetric ligands will be limited to one enantiomer only. However, synthetic (+)-zl9-THC (2) showed canna-bimimetic activity of 5-10% compared with that of the natural (-)-d9-THC (1) [19]. This observation cast doubt over the existence of a specific cannabinoid receptor and hence of a cannabinoid mediator. This presumed low degree of stereoselectivity and the above described suggestions and data on the actions of cannabinoids on membranes, delayed research aimed at the identification of a receptor-mediator cannabinoid system. 

Towards a biological target, the potency of two enantiomers can sometimes differ considerably and sometimes be very similar (Table 17.1). Often the activity is concentrated in only one enantiomer. When such a high stereoselectivity arises, it is admitted that the mechanism of action at the molecular level involves a highly specific interaction between the ligand — a chiral molecule — and the recognition site — a chiral environment. It is to be expected that the most active isomer, in terms of affinity, achieves a better steric complementarity to the receptor than the less active one. 

One of the hallmarks of receptor-mediated responses is the stereoselective interaction of ligands with their respective receptors and therefore structure-activity relationships (SARs) are used as evidence to support proposed receptor-media ted processes. Ihe SAR for PCBs have been extensively investigated and provide strong evidence for the role of the Ah receptor in initiating the toxic syndromes caused by PCBs and related compounds. 

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