Photophysics and Photochemistry of Imipramine, Desimipramine, and Clomipramine in Several Solvents: A Fluorescence, 266 nm Laser Flash, and Theoretical Study Carmelo Garcı ´a,* ,† Rolando Oyola, † Luis Pin ˜ ero, † Dionne Herna ´ ndez, † and Rafael Arce ‡ UniVersity of Puerto Rico at Humacao, Department of Chemistry, Humacao, Puerto Rico 00791, and UniVersity of Puerto Rico at Rı ´o Piedras, Department of Chemistry, San Juan, Puerto Rico 00936 ReceiVed: February 7, 2007; In Final Form: September 11, 2007 Imipramine (IPA) and its derivatives are used widely for the treatment of depression and other mental disorders. Although there are more than 20 FDA-approved antidepressant drugs, the search continues for better compounds with fewer deleterious side effects and higher efficacy. Over the past decade, several classes of antipsychotic drugs have been developed, whichsin spite of their structural diversitysshare an ability to modulate neurotransmission and to produce undesirable side effects. Phototoxicity is one of the most important side effects noted in treatment with tricyclic antidepressants (TCAs), but its mechanism has not yet been elucidated. To develop new knowledge regarding the relationship between the structure and the photophysics of these TCAs, we measured the photophysical properties of IPA, desimipramine (DIPA), and clomipramine (CIPA) in different solvents. The electronic configurations for the ground and the first excited singlet states were calculated using the AM1/RHF/CI and the AM1/RHF/HE semiempirical quantum theoretical methods, respectively. The ground-state properties are solvent-independent, while the emission maxima are red-shifted with increasing solvent polarity/polarizability. However, the fluorescence quantum yield is relatively low in all of the tested solvents ( f < 0.02). The primary transient intermediates produced by 266 nm high-intensity laser photolysis are the solvated electron and the corresponding radical cation, with a negligible contribution of triplet-triplet absorption. The properties determined for the primary transients generated with a 266 nm laser flash are consistent with the photodamaging effects generated through a limited radical mechanism. 1. Introduction The tricyclic antidepressant drugs (TCA)* imipramine (IPA, 1d), desimipramine (DIPA, 1e), and clomipramine (CIPA, 1f) belong to the dibenzazepine type (Figure 1). They are actually used in the management of neurogenic pain, attention-deficit hyperactivity disorder in children over age 6, depression, eating disorders, and panic or phobic disorders. These substances share a basic chemical structure comprising a three-ring core and an alkylamino side chain. Within the IPA family, as in the phenothiazines, the chlorinated derivative CIPA has the highest potency and the most pronounced side effects. 1,2 It produces, among others effects, allergic skin reactions (skin rash, urticaria), photosensitization, pruritus, edema, and drug fever. 3 The patients on CIPA treatment develop severe photodermatitis with associ- ated liver involvement, which might be the result of photoallergy and contact allergy to the drug. For the rest of the members of this family, light-induced effects are not remarkable and take much longer to appear. IPA, for example, produces only a slate- gray discoloration, which can last for years after cessation of the therapy. DIPA is the active in vivo metabolite of IPA and, as such, shares many of its pharmacological effects. DIPA produces a blue-gray cutaneous pigmentation after a period of 8 years of treatment. 4 These and other observations on several members of the TCA family lead to the conclusion that changes in the structure of these drugs do not only change their neuroleptic activity but they also change the spectrum and intensity of their side effects. Obata and Egashira 5 reported that IPA enhances the hydroxy radical formation induced by 1-methyl-4-phenylpyridium ion during enhanced dopamine overflow. It is also known that IPA and other TCAs inhibit monoamine oxidase (MAO) in vitro. 6 In dopamine nerve cells, free radicals are generated mainly by MAO through the deamination of dopamine and nonenzymati- cally by the autoxidation of dopamine. 7 Although the results of Obata and Egashira are related to dark reactions, these studies demonstrate the participation of IPA derivatives in electron- * Author to whom correspondence should be addressed. Address: University of Puerto Rico-Humacao, UPRH - Chemistry, 100 Road 908, Humacao, Puerto Rico 00791-4300. Phone: (787)-850-9387. Fax: (787)- 850-9422. E-mail: ca_garcia@uprh.edu. † University of Puerto Rico at Humacao. ‡ University of Puerto Rico at Rı ´o Piedras. Figure 1. Structure of the imipramine derivatives and the parent molecules. 168 J. Phys. Chem. B 2008, 112, 168-178 10.1021/jp0710739 CCC: $40.75 © 2008 American Chemical Society Published on Web 12/18/2007