| Inhibitors of phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28) are potential pharmacological tools for the study of the functions of epinephrine in the central nervous system. In this dissertation, a multifaceted approach employing SAR and crystallographic studies was used to design several series of compounds with the aim of preparing highly potent and selective inhibitors of PNMT that are able to cross the blood-brain barrier.; Varying the extent of fluorination on a series of highly potent, but nonselective, 3-methyl-THIQ inhibitors led to a dramatic increase in selectivity while maintaining potency. This increase in selectivity (decrease in alpha 2-adrenoceptor affinity) is apparently due to a decrease in the p Ka of the THIQ amine resulting from beta-fluorination and seems to be the first successful application of this approach for the design of selective pharmacological agents. 3-Difluoromethyl-7-substituted-THIQs have the proper balance of both steric and pKa properties and thus have enhanced selectivity versus the corresponding 3-fluoromethyl-7-substituted-THIQs and enhanced PNMT inhibitory potency versus the corresponding 3-trifluoromethyl-7-substituted-THIQs.; In an effort to increase the lipophilicity of a series of 3-fluoromethyl-7-( N-substituted aminosulfonyl)-THIQs, the sulfonamide nitrogen was replaced with a methylene group resulting in a series of 3-fluoromethyl-7-sulfonyl-THIQs. The sulfones were more lipophilic, but less potent, than their corresponding sulfonamides. This study aided in the identification of a potential hydrogen bond acceptor within the hPNMT active site, the main chain carbonyl oxygen of Asn39. The interaction of this residue with the sulfonamide---NH---is likely responsible for much of the enhanced hPNMT inhibitory potency of the sulfonamides versus the sulfones.; Based on SAR analysis of previously studied inhibitors and docking studies using the crystal structure of hPNMT, series of 7-substituted-1,2,3,4-tetrahydrobenz[ h]isoquinolines, 3-bromo-6-substituted-benzylamines and 2,6-disubstituted-4,5,6,7-tetrahydrothieno[3,2- c]pyridines were prepared and evaluated at PNMT. Although I had high hopes for these compounds, not a single one of them showed any potential as an effective inhibitor of PNMT. But ideas are like children: there are none so wonderful as your own. |
