The β3 adrenergic receptor is raising as an important drug target for the treatment of pathologies such as diabetes, obesity, depression, and cardiac diseases among others. Several attempts to obtain selective and high affinity ligands have been made. Currently, Mirabegron is the only available drug on the market that targets this receptor approved for the treatment of overactive bladder. However, the FDA (Food and Drug Administration) in USA and the MHRA (Medicines and Healthcare products Regulatory Agency) in UK have made reports of potentially life-threatening side effects associated with the administration of Mirabegron, casting doubts on the continuity of this compound. Therefore, it is of utmost importance to gather information for the rational design and synthesis of new β3 adrenergic ligands. Herein, we present the first combined 2D-QSAR (two-dimensional Quantitative Structure-Activity Relationship) and 3D-QSAR/CoMSIA (three-dimensional Quantitative Structure-Activity Relationship/Comparative Molecular Similarity Index Analysis) study on a series of potent β3 adrenergic agonists of indole-alkylamine structure. We found a series of changes that can be made in the steric, hydrogen-bond donor and acceptor, lipophilicity and molar refractivity properties of the compounds to generate new promising molecules. Finally, based on our analysis, a summary and a regiospecific description of the requirements for improving β3 adrenergic activity is given.
Leaf extracts of pepper, geranium, and jimsonweed inhibited the development of local lesions induced by tobacco mosaic virus (TMV) on Pinto bean leaves when mixed with the inoculum; sprayed on the underside of the leaf before inoculation of the upper surface; or sprayed on the upper leaf surface after inoculation. The extracts also inhibited lesion development on the primary leaf opposite to the one on which they were applied. The inhibitory activity of the geranium and pepper extracts was separated into two fractions; one with a molecular weight greater than 50 000 and one with a molecular weight range of 1000–50 000. The inhibitory activity of the jimsonweed extract was present in the high molecular weight fraction only. The high molecular weight fraction from pepper was inhibitory when applied to the underside of the leaf. This evidence, and that supplied by the jimsonweed extract, indicates that high molecular weight fractions are capable of inducing a systemic resistance even when applied to uninjured tissue.
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