| Popis: |
It was originally expected that LHRH and its agonist analogs would achieve therapeutic utility as pro fertility agents and conversely that antagonist analogs would find their niche as contraceptive agents (Schally and Kastin, 1971). Early findings, however, dramatically affected our thoughts, strategy and progress with these peptide agents. Firstly, it was found that agonist potency was particularly responsive to minor structural modification, e.g. substitution of d-amino acids in place of the sixth amino acid, glycine (Monahan et al., 1973), and replacement of the C-terminal glycinamide by alkylamide (Fujino et al., 1972). By virtue of increases in receptor binding affinity (Perrin et al., 1980) and in protection from metabolic degradation (Koch et al., 1977), extraordinarily potent analogs (superagonists) with potencies more than 200-fold greater than that of the natural hormone were achieved (Nestor et al., 1982). The second finding was that LHRH is required to act in a pulsatile, but low frequency, fashion for normal reproductive functioning or for pro fertility effects (Belchetz et al., 1978). Thus the fact that continuous infusion of LHRH (McNeil et al., 1979) or even once daily administration of ‘superagonists’ (Laron et al., 1981) (because of their longevity in vivo) results in ‘paradoxical’ antisteroidogenic and antireproductive effects could be explained as due to a desensitization of target cells in the pituitary (Heber et al., 1982) and possibly also at peripheral sites including the gonad (Hsueh and Jones, 1981). |
