Electric Literature of 42923-79-5, Chemistry is the science of change. But why do chemical reactions take place? Why do chemicals react with each other? The answer is in thermodynamics and kinetics.In a document type is Article, and a compound is mentioned, 42923-79-5, 7-Nitro-1,2,3,4-tetrahydroisoquinoline, introducing its new discovery.
Application of the goldilocks effect to the design of potent and selective inhibitors of phenylethanolamine N-methyltransferase: Balancing pKa and steric effects in the optimization of 3-methyl-1,2,3,4- tetrahydroisoquinoline inhibitors by beta-fluorination
3-Methyl-1,2,3,4-tetrahydroisoquinolines (3-methyl-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT), but are not selective due to significant affinity for the alpha2-adrenoceptor. Fluorination of the methyl group lowers the pKa of the THIQ amine from 9.53 (CH3) to 7.88 (CH2F), 6.42 (CHF2), and 4.88 (CF3). This decrease in pKa results in a reduction in affinity for the alpha2-adrenoceptor. However, increased fluorination also results in a reduction in PNMT inhibitory potency, apparently due to steric and electrostatic factors. Biochemical evaluation of a series of 3-fluoromethyl-THIQs and 3-trifluoromethyl-THIQs showed that the former were highly potent inhibitors of PNMT, but were often nonselective due to significant affinity for the alpha2-adrenoceptor, while the latter were devoid of alpha2-adrenoceptor affinity, but also lost potency at PNMT. 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. Using the “Goldilocks Effect” analogy, the 3-fluoromethyl-THIQs are too potent (too hot) at the alpha2-adrenoceptor and the 3-trifluoromethyl-THIQs are not potent enough (too cold) at PNMT, but the 3-difluoromethyl-THIQs are just right. They are both potent inhibitors of PNMT and highly selective due to low affinity for the alpha2- adrenoceptor. This seems to be the first successful use of the beta-fluorination of aliphatic amines to impart selectivity to a pharmacological agent while maintaining potency at the site of interest.
Balanced chemical reaction does not necessarily reveal either the individual elementary reactions by which a reaction occurs or its rate law.Electric Literature of 42923-79-5. In my other articles, you can also check out more blogs about 42923-79-5
Reference£º
Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem