Tertiary metabolites

In rats administered 2-bromoethylamine, urinary aziridine accounted for 15-45% of the dose. The carbamate 11.135 was not detected in urine, whereas oxazolidin-2-one and a tertiary metabolite, 5-hydroxy oxazolidin-2-one, accounted for 0 - 20% and 2 - 12% of the dose, respectively [156], The innocuity of oxazolidin-2-one led to the suggestion that either aziridine or 2-bromoethylamine itself is responsible for mitochondrial toxicity. These studies show that the nephrotoxic 2-haloethylamines undergo two competitive cyclizations with halide elimination, one probably a reaction of toxification, the other clearly a reaction of detoxification. 

The concept of primary and secondary metabolites is outlined and it is concluded that an exact definition is not especially useful. The coexistence of metabolites and the cellular machinery for their transformation is outlined by the concept of com-partmentation (Appendix 1). Tertiary metabolites and xenochemicals are defined for the sake of completeness (Section 2.1) and the current theories of the function of secondary metabolites are briefly discussed (Section 2.2). 

The tertiary metabolites seem to be devoid of any special biological activity of their own. They may conceivably be rendered active by mutations affecting their precursors and in this way gain access to the main biochemical events. If this happens they must eventually be subjected to regulatory systems such as enzymatic intervention. Their introduction into metabolic processes and their new activity demands means of regulation other than purely kinetic and thermodynamic control. 

It has been established that both the 17 hydroxy androgens rind estrogens, when administered orally, are quickly converted (o water-soluble inactive metabolites by intestinal bacteria, usually by reactions at the 17 position. It is this inactivation process that is largely responsible for the low-order oral potency observed with these agents. Incorporation of an additional car-l)on atom at the 17 position should serve to make the now tertiary alcohol less susceptible to metabolic attack and thus potentially confer oral activity to these derivatives. 

The above sequence mimics the proposed biosynthesis of Ervatamia alkaloids and in this context Thai and Mansuy (190) set out to determine whether an enzyme preparation would be able to promote the same transformation. By incubation of dregamine hydrochloride with a suspension of liver microsomes from a rat pretreated with phenobarbital (as a good inducer of P-450 cytochromes) in the presence of NADPH and 02, 20-epiervatamine (45) was formed together with the major metabolite Nl -demethyldregamine. It is well known that microsomal reaction on tertiary amines results in Af-oxide formation or N-deal-kylation. Thus it is likely that 45 was derived either from a rearrangement of dregamine JV4-oxide, catalyzed by the iron cytochrome P-450 or from one-electron oxidation of 30. 

Carbinolamines are chemically unstable and, in the case of tertiary amines, dissociate to generate the secondary amine and aldehydes as products or eliminate water to generate the iminium ion. The iminium ion, if formed, can reversibly add water to reform the carbinolamine or add other nucleophiles if present. If the nucleophile happens to be within the same molecule and five or six atoms removed from the electrophilic carbon of the iminium ion, cyclization can occur and form a stable 5- or 6-membered ring system. For example, the 4-imidazolidinone is a major metabolite of lidocaine, which is formed in vivo or can be formed upon isolation of the A -deethyl metabolite of lidocaine if a trace of acetaldehyde happens to be present in the solvent used for extraction (116,118) (Fig. 4.52). 

Amine oxides are readily reduced back to tertiary amines (Fig. 5.9). There are few drugs that are amine oxides, but there are many drugs that are tertiary amines and amine oxides are common metabolites. The amine oxide is often pharmacologically inactive however, because they are readily reduced back to tertiary amines, amine oxides can act as a buffer to the concentration of the tertiary amine. 

The situation is less promising with respect to dicarboxylated metabolites (CAPEC). Thus, reports on the presence of CAPECs in environmental samples have to deal with semiquantitative results because of the lack of any standard (see Chapter 5.1). For example Ding et al. [30] concentrated water samples from a tertiary effluent by rotary evaporation to dryness and, after derivatisation to propylesters, CAPECs were analysed by gas chromatography mass spectrometry... 

In rats dosed orally with the insect repellent N,N-diethyl-2-phenylacet-amide (4.57), TV-ethyl-2-phenylacetamide (4.58), 2-phenylacetamide (4.59), and 2-phenylacetic acid (4.60) were found as metabolites in the blood, liver, and kidney [35], Hydrolysis of this tertiary amide is, perhaps, facilitated by the presence of the aromatic ring. Indeed, a similar metabolic pattern has been found for the aromatic amide TV,TV-diethyl-3-methylbenz amide (4.82) (see Sect. 4.3.1). 

A simple example in this class with which to begin is A,A-diethyl-m-to-luamide 0V,/V-dicthyl-3-mcthylbenzamidc, DEET, 4.82), an extensively used topical insect repellant. The hydrolysis product 3-methylbenzoic acid was detected in the urine of rats dosed intraperitoneally or topically with DEET. However, amide hydrolysis represented only a minor pathway, the major metabolites resulting from methyl oxidation and A-dealkylation [52], Treatment of rats with /V,/V-dicthylbcnzamidc (4.83), a contaminant in DEET, produced the same urinary metabolites as its secondary analogue, A-ethylbenzamide (see Sect. 4.3.1.2). This observation can be explained by invoking a metabolic pathway that involves initial oxidative mono-A-deethylation followed by enzymatic hydrolysis of the secondary amide to form ethylamine and benzoic acid [47], Since diethylamide was not detected in these experiments, it appears that A,A-diethylbenzamide cannot be hydrolyzed by amidases, perhaps due to the increased steric bulk of the tertiary amido group. 

N - Benzyl- N -p icolinoylpiperazine (EGYT-475, 4.88), a compound with potential antidepressant activity, underwent similar hydrolysis. After intravenous administration, picolinic acid (4.89) was one of its major urinary metabolites in rats the other product, A-benzylpiperazine (4.90) was also detected, but at much lower levels, since it was further transformed by A-de-benzylation [55], Since the products of direct hydrolysis of these cyclic tertiary amides (i.e., the corresponding secondary amines) were found at substantial levels, it appears that oxidative A-monodealkylation is not an essential step for hydrolysis in these compounds, in contrast to the findings for A,A-diethylbenzamide. This contradicts the hypothesis [52] (see above) that the steric bulk of the tertiary amide group impedes direct hydrolysis. Here, although the degree of steric bulk is at least comparable, direct hydrolysis clearly takes place. 

Tertiary arylacetamides appear to undergo hydrolysis to a very limited extent only. Hydrolysis of the synthetic opioid fentanyl (4.117) to despropa-noylfentanyl (4.118) was a very minor pathway in humans [76], No metabolites resulting from amide hydrolysis were detected for the fentanil analogues alfentanil (4.119) and sufentanil (4.120) [77], for which oxidative N-dealkylation was the main metabolic pathway. 

The cyclic metabolite 11.169 was also a substrate in further biotransformations, being (V-demethylated to the corresponding endocyclic imine, and oxidized to phenolic metabolites. Very little if any of the secondary amine metabolite (11.168) appeared to undergo direct (V-demethylation to the primary amine, in contrast to many other tertiary amines, presumably due to very rapid cyclization of the secondary amine facilitated by steric and electronic factors. The possibility for the iminium cation (11.169 H+) to become deprotonated (a reaction impossible for the iminium 11.166 in Fig. 11.20) should also drive the cyclization reaction. 

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

Inhibition mechanisms by A/-cyclopropyl MPTP analogues are also discussed in terms of two catalytic pathways, one of which is based on an initial SET step from the nitrogen lone pair, as proposed by Silverman, and the second is based on an initial a-carbon hydrogen atom transfer (HAT) step, as proposed by Edmondson, leading to a radical and dihydropyridinium product formation. The observation that MAO B catalyzes the efficient oxidation of certain 1-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridines to the corresponding dihydropyridinium metabolites suggests that the catalytic pathway for these cyclic tertiary allylamines may not proceed via the putative SET-generated aminyl radical cations [122], Further studies will be necessary to clarify all the facets of the mechanism of inhibition of MAO by cyclopropylamines. 

SSRI medications differ greatly in their chemical structures and composition. For example, citalopram is a tertiary amine with 2 N-metabolites. All three com-... 

The local anesthetics are converted in the liver (amide type) or in plasma (ester type) to more water-soluble metabolites, which are excreted in the urine. Since local anesthetics in the uncharged form diffuse readily through lipid membranes, little or no urinary excretion of the neutral form occurs. Acidification of urine promotes ionization of the tertiary amine base to the more water-soluble charged form, leading to more rapid elimination. 

The TCAs resemble the SNRIs in function, and their antidepressant activity is thought to relate primarily to their inhibition of 5-HT and norepinephrine reuptake. Within the TCAs, there is considerable variability in affinity for SERT versus NET. For example, clomipramine has relatively very little affinity for NET but potently binds SERT. This selectivity for the serotonin transporter contributes to clomipramine s known benefits in the treatment of OCD. On the other hand, the secondary amine TCAs, desipramine and nortriptyline, are relatively more selective for NET. Although the tertiary amine TCA imipramine has more serotonin effects initially, its metabolite, desipramine, then balances this effect with more NET inhibition. 

The enzyme found in the liver will deaminate secondary and tertiary aliphatic amines as well as primary amines, although the latter are the preferred substrates and are deaminated faster. Secondary and tertiary amines are preferentially dealky la ted to primary amines. For aromatic amines, such as benzylamine, electron-withdrawing substituents on the ring will increase the reaction rate. The product of the reaction is an aldehyde (Fig. 4.30). Amines such as amphetamine are not substrates, seemingly due to the presence of a methyl group on the a-carbon atom (Fig. 4.27). Monoamine oxidase is important in the metabolic activation and subsequent toxicity of allylamine (Fig. 4.31), which is highly toxic to the heart. The presence of the amine oxidase in heart tissue allows metabolism to the toxic metabolite, allyl aldehyde (Fig. 4.31). Another example is the metabolism of MPTP to a toxic metabolite by monoamine oxidase in the central nervous system, which is discussed in more detail in chapter 7. 

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