Buspirone substructures

To assist with the MS/MS structure identification, the gross substructure of buspirone is categorized into profile groups (Kerns et al., 1995). Profile groups directly correlate specific product ions and neutral losses with the presence, absence, substitution, and molecular connectivity (Lee et al., 1996) of specific buspirone substructures and their modifications. The profile groups of buspirone are identified with abbreviations that correspond to the three specific substructures azaspirone decane dione (A), butyl piperazine (B), and pyrimidine (P). Substituted substructures are designated with a subscript ( ), and a dash (-) denotes substructure connectivity. Thus, the buspirone molecule is represented by A-B-P. The As-B-P designation... 

For example, full-scan mass spectra of buspirone contain an abundant [M+H]+ ion signal with little detectable fragmentation. The product ion spectrum reveals product ions and neutral losses associated with diagnostic substructures of buspirone (Figure 6.25). The product ion at mlz 122, for example, is indicative of the pyrimidine substructure. The presence of this ion in the product ion spectrum of a metabolite indicates a structure that contains the pyrimidine substructure. Similarly, the mlz 180 product ion is diagnostic of the azaspirone decane substructure, and the neutral loss of 164 (producing the mlz 222 product ion) is diagnostic of the butyl azaspirone decane dione substructure. 

Figure 6.25 Product ion spectrum of the [M+H]+ of buspirone, and the correspondence of ions to specific substructures that are diagnostic of the compound and are used as a template for structure identification of buspirone metabolites. (Reprinted with permission from Kerns et al., 1997. Copyright 1997 Elsevier.)...

Table 6.11 illustrates a representative buspirone metabolite structure database. Information on the structure, molecular weight, UV characteristics, RRT, and product ions of metabolites obtained from rat bile, urine, and liver S9 samples are compiled. Using this format, the predominant buspirone metabolite profile groups, As-B-P, A-B-Ps, and As-B-Ps are easily recognized. These profile groups indicate azaspirone decane dione and pyrimidine as metabolically active sites of attack and the presence of multiple substitution sites on each of these substructures. In many cases, the profile groups indicate the occurrence of metabolic reactions on more than one substructure. 

Full-scan mass spectra generally contain an abundant [M - - H] ion signal with little detectable fragmentation. Product-ion spectra are obtained to reveal product ions and neutral losses that are associated with diagnostic substructures of the buspirone molecule. 

The concept can be illustrated by the identification of the metabolites of the anxiolytic drag buspirone [1, 12]. Buspirone (Figure 10.2b) is considered as a combination of three subgroups the azaspirone decane dione (A), the butyl piperazine (B), and pyrimidine (P). Whereas buspirone itself is annotated at A-B-P, a metabolite with a substitution in the pyrimidine ring can be indicated as A-B-P. It was found that in buspirone the azaspirone decane dione and the pyrimidine part of the molecule are prone to (multiple) substitution, such as hydroxylation, hydroxylation and methoxylation, and glucuronidation. The loss of the complete substructure is also observed. In this way, a total number of 26 buspirone metabolites were identified and categorized. 

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