A) Chemical structure, physical-chemical and physical properties of drugs
Drug properties depend on their chemical structure, presence of functionally active groups and shape and size of their molecules to a significant extent. The effective interaction of a drug with a receptor requires a structure that provides their closest contact. The strength of intermolecular bonds depends on the degree of drug-receptor proximity. Thus, it is known that in an ion bond the electrostatic attraction of two opposite charges are in inverse proportion to the squared distance between them, and Van der Waals forces are in an inverse proportion to 6-7th power of distance (see Table II.3).
The spatial relationship of a drug with a receptor, i.e. complementarity, is especially important for their interaction. It is confirmed by differences in the activity of stereoisomers. Thus, D(+)-epinephrine substantially yields in activity to L(-)-epinephrine in its effect on arterial pressure. These compounds are distinguished by the spatial relationship of molecular structural elements that have a key significance for their interaction with adrenoceptors.
If a drug has several functionally active groupings it is necessary to take into account the distance between them. Thus, in the series of bis-quaternary ammonium compounds (CH3)3N+-(CH2)n-N+(CH3)3 ? 2X- for ganglion blocking action n=6 is optimal, while n=10 and 18 are optimal for neuromuscular block. It indicates a definite distance between anionic structures of nicotinic cholinoceptors with which ion bonding of quater-
nary nitrogen atoms occurs. Other important factors for such compounds are radicals, «screening» cation centers, the size of positive atom and charge concentration, as well as the structure of the molecule that connects cation groupings.