Frank Momany

Computer-Assisted Modeling of Xenobiotic Growth Hormone Secretagogues

Growth hormone releasing peptides (GHRPs) are chemically synthesized and designed entities with no sequence relationship to any known peptide hormone (1–4). Unusual in the realm of drug design, they are peptides that have been invented prior to the discovery of the endogenous peptide hormone. In fact after more than 13 years of study, the putative GHRP-like hormone and its receptor have yet to be isolated. Further, GHRPs act in fundamentally different ways than GHRH, as described by Bowers et al. (5), and synergistically release GH when administered together with GHRH. The endocrinology and structure/activity relationships of GHRPs pose challenging problems to scientists, and answers are being actively pursued.

Antiovulatory Potency and Conformation of an Antagonist of the Luteinizing Hormone-Releasing Hormone Having Six D-Amino Acids

Abstract [N-Ac-Thr 1 ,D-Phe 2,D-Trp 3,6]-LHRH was the model antagonist of LHRH, which was the basis for tho design, synthesis and bioassay of seven peptides having four, five and six D-amino acids, which resulted from three single, three double, and one triple introductions of D-amino acids in positions 4, 5 and 8 of the model. Only the analog with six D-amino acids, [N-Ac-Thr 1,D-Phe 2 ,D-Trp 3,D-Ser 4, D-Tyr 5 ,D-Trp 6 ,D-Arg 8]-LHRH, had antiovulatory activity which was higher than that of the model antagonist, i.e., 70% antiovulatory activity at 25 μg/rat compared with 50% activity at 50 μg/rat, respectively. Empirical energy calculations gave a conformational structure for [N-Ac-Thr 1,D-Phe 2,D-Trp 3, D-Ser 4,D-Tyr 5,D-Arg 6,D-Arg 8]-LHRH which is similar to that calculated for previous potent antagonists. These results are a basis of new designs of antagonists having D-sub-stituents in up to ten positions toward effective inhibitors of ovulation by the parenteral and oral routes of administration.