DEVELOPMENT OF L-THREO-DOPS, A NOREPINEPHRINE PRECURSOR AMINO-ACID

threo-Dihydroxyphenylserine (DOPS) is a synthetic amino acid which can be decarboxylated by L-aromatic amino acid decarboxylase to yield nat ural form of norepinephrine(l-NE), a principal neurotransmitter in bot h central and peripheral (sympathetic) nervous systems. Like L-Dopa as an agent for dopamine precursor therapy, DOPS was expected to have a potential as an agent for NE precursor therapy. Previous studies carri ed out by several groups in early 1970s, however, reached a negative c onclusion that threo-DOPS was not an effective precursor of NE in the brain because of its low NE-increasing activity and weak pharmacologic al action. Since the latter half of 1970s, on the contrary, three Japa nese research groups have successfully shown the possibility of DOPS a s a useful NE-precursor. That is, Tanaka (Kobe Univ.) showed that L-th reo-DOPS is the real I-NE precursor among four DOPS-enantiomers, and t hat it has several pharmacological activities such as a slow-onset and long-lasting presser effect, an inhibitory effect on harmaline-induce d tremor and so on. Hayashi and Suzuki (Osaka Univ.) found through the mobidity study on familial amyloid polyneuropatchy (FAP) that the pro gress of the disease develops NE-deficiency (NE-D), that severe orthos tatic hypotention in FAP might be due to NE-D, and that L-DOPS has fav orable effects on this symptom. Narabayashi (Juntendo Univ.) found tha t NE-D develops in patients with advanced Parkinson's disease (PD), th at a freezing phenomenon in these patients might be associated with NE -D, and that L-DOPS improves the phenomenon. Based on these findings, the development of L-DOPS for registration had been undertaken by Sumi tomo Pharmaceuticals Co., and an approval was given to it in 1989 as a n agent for the treatment orthostatic hypotention in FAP or Shy-Drager syndrome and freezing phenomenon in PD. Preclinical and clinical stud ies done in the R & D confirmed that L-DOPS markedly restored NE-D and improved related-syndrome in the NE-deficient animals/patients, and t hat its actions were slow-onset, long-lasting and gentle. The R & D of L-DOPS described in this paper includes studies on industrial product ion, efficacy pharmacology (mode of action), metabolism and clinical t rial of this agent.