Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 1. Chloro-Substituted 1,2,3,4-tetrahydroisoquinolines

Caldwell

et al. 1999

J. Med. Chem.

An enantiospecific method was developed for the synthesis of 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines (THIQs) from phenylalanine. Biochemical evaluation of the enantiomers of these compounds at both PNMT and the alpha(2)-adrenoceptor indicates that both sites display similar stereoselectivity. Overall the R-enantiomer was usually the more potent enantiomer at both PNMT and the alpha(2)-adrenoceptor for these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-THIQs. The one exception is 3-hydroxymethyl-7-nitro-THIQ (9), which was found to display the opposite stereoselectivity at the alpha(2)-adrenoceptor. A comparison of the PNMT inhibitory potency of the enantiomers of these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-THIQs indicates that all of the 3-substituted-THIQs displayed similar inhibitory potency for PNMT. However, the nature of the 3-substituent was found to have a major effect on the alpha(2)-adrenoceptor affinity of these compounds with the 3-hydroxymethyl- and 3-fluoromethyl-THIQs having the highest affinity and THIQs containing the 3-chloromethyl moiety the least. Compounds R-3-fluoromethyl-7-cyano-THIQ (R-12) and R-3-fluoromethyl-7-N-(4-chlorophenyl)aminosulfonyl-THIQ (R-13) and both enantiomers of 3-chloromethyl-7-nitro-THIQ (R- and S-30) are the most selective inhibitors in this study and display selectivities (alpha(2)-adrenoceptor K(i)/PNMT K(i)) greater than 200. These compounds give important insight into the steric and stereochemical preferences of both PNMT and the alpha(2)-adrenoceptor, which should assist in the development of new PNMT inhibitors.

Section: Chemistrymentioning

confidence: 99%

Enantiospecific Synthesis of 3-Fluoromethyl-, 3-Hydroxymethyl-, and 3-Chloromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of Phenylethanolamine N-Methyltransferase versus the α₂-Adrenoceptor

Caldwell

et al. 1999

J. Med. Chem.

“…Previous studies have shown that constraining the methylamine side chain of benzylamine (15) to form THIQ (5) increases its hPNMT inhibitory potency 29-fold. 16 Because 18 was found to be more potent and selective for hPNMT than 15, we predicted that constraining the side chain of 18 into a 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (THTP, 14) ring system would likely result in superior hPNMT inhibitory potency and selectivity versus 5.…”

Section: Introductionmentioning

confidence: 99%

“…Because the THIQ nucleus can be viewed as either a constrained benzylamine or a constrained 2-phenylethyl-amine and a common isosteric replacement for a benzene ring is a thiophene ring, the commercially available thiophene analogs of benzylamine (15) and 2-phenylethylamine (16) were evaluated at hPNMT and the α 2 -adrenoceptor ( Table 2). As expected, 2-(2-thienyl)ethylamine (19) was found to have hPNMT inhibitory potency that was similar to phenylethylamine 16.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines and comparison with their isosteric 1,2,3,4-tetrahydroisoquinolines as inhibitors of phenylethanolamine N-methyltransferase

Bioorganic & Medicinal Chemistry

Seim

Bhat

et al. 2008

A series of substituted 4,5,6,7-tetrahydrothieno[3,2-c]pyridines (THTPs) was synthesized and evaluated for their human phenylethanolamine N-methyltransferase (hPNMT) inhibitory potency and affinity for the α 2 -adrenoceptor. The THTP nucleus was suggested as an isosteric replacement for the 1,2,3,4-tetrahydroisoquinoline (THIQ) ring system on the basis that 3-thienylmethylamine (18) was more potent as an inhibitor of hPNMT and more selective towards the α 2 -adrenoceptor than benzylamine (15). Although the isosterism was confirmed, with similar influence of functional groups and chirality in both systems on hPNMT inhibitory potency and selectivity, the THTP compounds proved, in general, to be less potent as inhibitors of hPNMT than their THIQ counterparts, with the drop in potency being primarily attributed to the electronic properties of the thiophene ring. A hypothesis for the reduced hPNMT inhibitory potency of these compounds has been formed on the basis of molecular modeling and docking studies using the X-ray crystal structures of hPNMT co-crystallized with THIQ-type inhibitors and S-adenosyl-L-homocysteine as a template.

“…Overall, these 4-fluoro-THBAs (12)(13)(14) were found to be more selective than similarly substituted 3-fluoromethyl-THIQs with the exception of nitrile 15. 4-FluoroTHBAs containing hydrophilic electron-withdrawing 8-substituents (13 and 15) were found to be selective inhibitors of PNMT as anticipated.…”

Section: Discussionmentioning

confidence: 98%

Synthesis and Evaluation of 4-Fluoro-8-substituted-2,3,4,5-tetrahydro-1H-2-benzazapines as Selective Inhibitors of Phenylethanolamine N-Methyltransferase versus the α₂-Adrenoceptor

Caldwell

et al. 2001

J. Med. Chem.

A small series of 4-fluoro-8-substituted-2,3,4,5-tetrahydro-1H-2-benzazapines (4-fluoro-THBAs; 12-15) were synthesized and evaluated as inhibitors of phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28) and as inhibitors of the binding of clonidine at the alpha(2)-adrenoceptor. 4-Fluoro-THBAs 13-15 displayed selectivity ratios (alpha(2) K(i)/PNMT K(i)) greater than 75 and 4-fluoro-8-nitro-THBA (13) was found to be one of the most selective inhibitors of PNMT known, with a selectivity ratio of greater than 900. These compounds are also quite lipophilic and according to previous results from this laboratory should be able to penetrate the blood-brain barrier. These 4-fluoro-THBAs represent important leads in the development of new, more selective, CNS-active inhibitors of PNMT.