Aromatic Amino Acid Hydroxylase Inhibitors. Halogenated Phenylalanines
1. I
X comparisoii I J f all the riiig isonieric halopheriylalatiiiies inhibitors of pheriylalaiiirie aiid t.yro4tie hytiriisyl:we revealed that optimal iiihihitioti was achieved with 3-iodopheiiylalaiiiIie. a-llethylation of the 3-halopheiiylalaniiies was fourid to eiihniice iiihibition of 1.yrosiiie hydroxylase, but have no effect, on phenylalaniiie hydroxylase. The implic.at,iotis o f these findings are discussed.
One of the approaches to antihypertensive clrugs has been to syiithesize :gents which inhibit the biosynthesis of iiort.piiiephriiic. Although several enzymwtic steps :ire avai1:ible for. pharmacological control, the demonstixtiori b\- Udenfrietid and coworl\-ers2that tyrosinr. hyclrosylase represerits thc r:tte-limitiiig step in norepinephrine biosynthesis has stimuhted iiitereet i n inhibitors of this enzyme. ;\lthough it number of inhibitors of th-rosiiie hydroxylase have been described, a, a-met hylt ~rrosinehas beer] the most thoroughly irivestigatcd from i i cliiiical st:mdpoint. I t has not only become i i valuable pharmacological :tud biocllemic:il tool, but :ilso ;m cfiectivc agent foi, the tre:rtment of pheochromoc?.toni:i.~ On tho o t h w harid, this drug i loir1~-met:~bolizedt o a-meth. iiiitl a-methylno inephrinc which ni:i~. mod overall I)hai'niacologic:rl wtioli particularly I I ~ O I I chrotiic :idniiriistr.:ttion.~ b'or t h b i*e;~son,current i l l tcrcst is focused on competitive inhibitors OF tyrosinc I1ytlroxyl:ise which are not metabolized to catechols. .\Iorrovcr, i t is importnrit that the iiihibitorr be select i w for t\.rosilie hydroxylase :iritl not interfcrc with thc other :irom:Ltic imino x i d kiydroxyl:\ses;. ('oncomit:irit itiliibitioii of pheiiy1:iI:iiiiIi~ Ii>-tiroxylase, for t x :iniiil(l, \roultl induce :I s t a t e of phcn~.ll;ctonuri:i whey intmd'crencc with tryptophaii hyclroxyluse would mo br:tiii s(wtoiiin levels. I t is for this re:isoii that scveixl y w i :igo ~ we initiated :i 1)rogrtitni \\-hich nould attempt t o tlc.filict and distinguish tlw structiiral features L'Cq t i i r d for inhibition of t h v various :irornatic :tmirio acid h~~clrosyl:ises.13ec:~iisoof t h numerous reports clcAiig \vith the iriliibitory properties of p-fluoropheti).l:il:iiiiiw and p-chloropheriylcllaniiiiii~~~ our first ($fort involvcd t he comp;irisori of all thc. isomeric Ii:ilogen:\tcd i s inhibitors of the :ironiatic :imino i t c i t i I t K:W hoped that such studies w o i i l d * 'l'ri
xi liiitn
lead t o :i better uiiderstanding of the nature of tliv :wtive sites arid provide information that would bv v:iluable for the design of selective inhibitor\ The htilogenatecl pheriyla1:tniiies were obtained conim e r c i d l ~ or synthesized :iccording t o published procedureb. Opticnlly :ictive X-iodophr~ri\-l:ilanirle w:~\ obtained by fractiomil cry4allizutioti of the dinstcreoi-omeric >:ilts formed by treating t hr M-acetyl deriwitive with I-amphetamine. The a-methyl :imino acid thesized from the appropriate ketoiic. of the 111 dmtoiri IT-. l
