Sampson, Julia H.; (1996) The search for analgesic compounds from higher plants. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Many important modern day plant drugs have been discovered by following leads from traditional folk use. The aim of this work was to select plants from the medicinal and scientific literature of China, the West Indies, South America and West Africa, which have been used traditionally for the treatment of pain and to screen them in the bradykinin BK II and calcitonin gene-related peptide (CGRP) binding assays in an attempt to find new leads to analgesic compounds. More than twenty endogenous neuropeptides have been implicated in the mediation of pain within the mammalian central nervous system including bradykinin, CGRP and Substance P. The bradykinin BK II and CGRP in vitro radioligand binding assays were developed in order to screen plant extracts for new leads to analgesic compounds. Bradykinin is involved in the mediation of acute pain and a number of bradykinin peptide antagonists are available for in vivo and in vitro use, but there is a need for antagonists which are selective and stable in vivo. CGRP is thought to be a mediator of migraine and other vascular headaches and there is no single drug to prevent the development of migraines after the initial onset. Thus new non-peptide lead molecules to CGRP antagonists are required. The plant extracts which produced positive activity in the assay were treated with polyvinylpyrrolidone (PVP) to remove tannins, thus reducing the possibility of obtaining false positive results due to the non-specific binding of tannins to proteins. Three hundred ethnomedically selected plants and 335 randomly collected plants yielded 21 plants with apparent specific activity in the bradykinin BK II assay, of which 19 were ethnomedically selected. Five plants had selective activity in the CGRP assay. The extract of Symplocos leptophylla produced the most potent and selective inhibition of the BK II receptor and was chosen for further investigation in attempts to determine the active principle(s). The extracts of Ipomea pes-caprae and Panax ginseng inhibited binding of bradykinin to the BK II receptor and Substance P to the Neurokinin 1 receptor, and were thus deemed to be non-selective in the BK II assay. The extracts were tested in mice in the in vivo acetic acid writhing test and I. pes-caprae was found to significantly decrease the number of writhes when compared to control values, thus I. pes-caprae may have some broad based analgesic effects. Low throughput screens such as the bradykinin BK II and CGRP assays may be used in conjunction with ethnobotanical literature as a means of identifying plant derived natural products as leads to new analgesic compounds.

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