A series of analogs of
gonadotropin-releasing hormone (
GnRH) containing the conformationally restrictive residue
tetrahydroisoquinoline carboxylic acid (
Tic) or its non-restricted parent
phenylalanine were synthesized and evaluated for anti-ovulatory activity in the rat. The series, based on the potent linear parent compound Ac-DNal1-DCpa2-DPal3- Ser4-Tyr5-DPal6-Leu7-Arg8-Pro9-DAla10-NH2, included L-
Tic in positions 1, 2, 3, 7 and 9, D-
Tic in positions 1, 2, 3, 6 and 9, or D-Phe in positions 2 and 3 for comparison. The most potent analog in this series, with D-
Tic in position 6, fully inhibited ovulation at 2.5 micrograms compared to near complete inhibition at 0.5 microgram for the parent compound. A theoretical analysis of the conformational restrictions imposed on mainchain and sidechain torsional angles by the incorporation of
Tic was conducted in vacuo using molecular mechanics techniques. Using cyclo(4-10)-[Ac-delta 3Pro1,DCpa2,DTrp3,Asp4,DNal6,Dpr10]-
GnRH as a template conformer for which NMR conformational data is available, it was found that the potency of the different analogs correlated with the strain energy required to deform the mainchain and backbone angles of residues to values which would be expected if
Tic were present and if the analog assumed the same
solution structure. In particular, the effect of
DTic at position 6 is to maintain the type II' beta-turn involving residues 5-8 found in active
GnRH analogs.