Coordination Chemical Aspects of Receptor Biochemistry
Recently, radioassay techniques have been developed characterizing the pharmacological properties of the specific binding of endogenous and drug ligands to synaptic membranes. However, biochemical and physico-chemical properties of such binding sites (receptors) are not fully understood. Therefore, a number of partly contradictory biochemical models have been developed. The physico-chemical properties of the chemical structures involved are usually neglected. These intermolecular binding between a “receptor” and a ligand can be described at the molecular level as interactions between an electron pair donor (EPD) and an electron pair acceptor (EPA). The binding between transmitter and “receptor” is expected to be strongest when the “receptor” binding sites are complementary to those of the transmitter. Following this concept, the structure of the membrane is suggested to be such that the polar groups form a three dimensional network, in which EPD sites (of the polar groups) interact with EPA sites.
We have used this model to explain some of the interactions between 5-hydroxytryptamine (5-HT), the “5-HT receptor”, NH 4 + and L-valine. As the rate of 5-HT binding increases at higher temperature (indicating the need of activation energy) it is concluded that the receptor sites normally are covered with something, e.g. polar groups of the membrane or water. Neuro-toxic ammonia reduces 5-HT binding sites and this effect is related to the EPD strength of NH 4 + being comparable to that of 5-HT. Similarly the effect of L-valine on 5-HT binding can be attributed to the (relative) strength of their EPD sites.
The stimulation of L-valine binding in the presence of Ca++, Mg++ or Ba++ ions and the inhibition of L-valine binding by Na+, K+ and NH 4 + indicates the close relationship between the binding site(s) for valine and the flux of cations across the membrane. Divalent ions are weakening the bonds within the membrane. This EPD-EPA model of a membrane does not necessarily need “localized” ion channels. The passive ion flux across the membrane from the outer to the inner membrane sites appears to occur preferentially at sites where the strength of the barrier is diminished. Pathophysiological changes directed preferentially to (a) certain transmitter system(s) (synaptic membrane structure[s]) can be explained by this alternative model of a EPD-EPA concept.
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- Authors’ address: Prof. Dr. H. Noller Institut für Physikalische Chemie, Technische Universität Wien, Getreidemarkt 9, A-1060 Wien, Austria.Google Scholar