1-Methyl-1,2,3,4-Tetrahydroisoquinoline, an Endogenous Amine with Unexpected Mechanism of Action: New Vistas of Therapeutic Application

Lucyna Antkiewicz-Michaluk 0 Agnieszka Wasik 0 Jerzy Michaluk 0 0 L. Antkiewicz-Michaluk (&) A. Wasik J. Michaluk Department of Neurochemistry, Institute of Pharmacology Polish Academy of Sciences , Smetna Str.12, 31-343 Krakow, Poland This review outlines the effects of 1,2,3,4-tetrahydroisoquinoline (TIQ) and its derivative, 1-methyl1,2,3,4-tetrahydroisoquinoline (1MeTIQ), endogenous substances imbued with high pharmacological potential and broad spectrum of action in brain. 1MeTIQ has gained special interest as a neuroprotectant, and its ability to antagonize the behavioral syndrome produced by well-known neurotoxins (e.g., MPTP; rotenone). This review is thus focused on mechanisms of action of 1MeTIQ in behavioral, neurochemical, and molecular studies in rodents; also, effects of TIQ and 1MeTIQ on dopamine metabolism; and neuroprotective properties of TIQ and 1MeTIQ in vitro and in vivo. Finally, antiaddictive properties of 1MeTIQ will be described in cocaine self-administered rats. Findings implicate TIQ and especially its methyl derivative 1MeTIQ in unique and complex mechanisms of neuroprotection in various neurodegenerative illnesses of the central nervous system. We believe that MAO inhibition, free radicals scavenging properties, and antagonism to the glutamatergic system may play an essential role in neuroprotection. In addition, the results strongly support the view that 1MeTIQ has a considerable potential as a drug for combating substance abuse, through the attenuation of craving. - 1,2,3,4-Tetrahydroisoquinoline (TIQ) is a member of a family of tetrahydroisoquinolines widespread in plant and animal and human brains (McNaught et al. 1998; Rommelspacher and Susilo 1985). In most cases, tetrahydroisoquinolines can be formed as condensation products of biogenic amines (i.e., phenylethylamines and catecholamines) with aldehydes or a-keto acids by the so-called PictetSpengler reaction (Rommelspacher and Susilo 1985; Zarranz de Ysern and Ordonez 1981; Nagatsu 1997; McNaught et al. 1998), although some of them may be also synthesized enzymatically (Yamakawa and Ohta 1997, 1999; Naoi et al. 2004). The tetrahydroisoquinoline family can be divided into compounds with catechol- and non-catechol structure. TIQ is the simplest representative of the group of non-catechol tetrahydroisoquinolines which occur naturally in plants and in a variety of food products (Makino et al. 1988; Niwa et al. 1989) as well as in the brain of humans, primates, and rodents (Kohno et al. 1986; Makino et al. 1988; Niwa et al. 1987; Ohta et al. 1987; Yamakawa et al. 1999). For the first time, tetrahydroisoquinolines attracted considerable attention of neurochemists and pharmacologists when Davis and Walsh (1970) demonstrated that the alcohol metabolite acetaldehyde promoted in vitro conversion of [14C]dopamine into [14C]tetrahydropapaveroline (THP). Simultaneously, THP was identified in the urine of parkinsonian patients on L-DOPA (3,4-dihydroxyphenylalanine) medication (Sourkes 1971; Sandler et al. 1973; Matsubara et al. 1992) and in the urine and brain of rats treated with LDOPA (Turner et al. 1974). Almost at the same time, salsolinol (6,7-dihydroxy-1-methyl-1,2,3,4-TIQ), an adduct of dopamine and acetaldehyde, was identified in the urine of non-pathologic human volunteers, occurring at high concentrations in the urine of intoxicated alcoholics (Collins et al. 1979) and in brains of rats treated with ethanol (Collins and Bigdeli 1975). Although TIQ has been proposed to be one of the etiological factors of Parkinsons disease (PD), its implication in the pathogenesis is not clear, in contrast to other tetrahydroisoquinolines with rather neurotoxic mechanism of action in the brain, e.g., salsolinol or 1-benzyl1,2,3,4-TIQ (1BnTIQ). Early studies on tetrahydroisoquinolines revealed their neuroleptic-like properties (Ginos and Doroski 1979) and our more recent results suggest that TIQ and its derivatives are antagonists of agonistic conformation of the dopamine D2 receptor (Antkiewicz-Michaluk et al. 2007; Vetulani et al. 2001, 2003a). This explains why TIQ and its congeners effectively block dopaminergic stimulation without affecting much the basal locomotor activity. Pharmacologically tetrahydroisoquinolines aroused also an interest as potential NMDA (N-methyl-D-aspartate) receptor antagonists (Ortwine et al. 1992). Some of them were described as effective antagonists of the phencyclidine (PCP) site (Rogawski et al. 1989). However, most tetrahydroisoquinolines do not substitute for PCP (Nicholson and Balster 2003). Apart from TIQ, this group encompasses also, the methyl derivative of TIQ, 1-methyl-1,2,3,4-TIQ (1MeTIQ), is a neuroprotective compound. Among several endogenous TIQs 1MeTIQ has a special position, as very early it was described in the brain (Kohno et al. 1986; Makino et al. 1990; Niwa et al. 1987; Ohta et al. 1987), and shortly thereafter recognized as a potential antiparkinsonian agent on the basis of reversal of bradykinesia induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), TIQ, or 1BnTIQ (Tasaki et al. 1991; Kotake et al. 1995). 1-MeTIQ was identified in normal rat brains in 1986 (Kohno et al. 1986), and subsequently found to be present in foods rich in 2-phenylethylamine, from which it may enter the brain (Makino et al. 1988). However, it is also synthetized enzymatically in the brain from 2-phenethylamine to pyruvate (Niwa et al. 1990; Tasaki et al. 1993; Yamakawa and Ohta 1997). Having an asymmetric carbon atom, 1MeTIQ may appear in the form of R- and S-stereoisomers, and the product found in brain and in foods is a racemate (Makino et al. 1990), although the stereoisomers do not much differ in their biological actions (Abe et al. 2001; Wasik et al. 2012). 1MeTIQ unlike several other TIQs displays neuroprotective and antiaddictive properties which will be particularly emphasized in this article (Antkiewicz-Michaluk and Vetulani 2001; AntkiewiczMichaluk et al. 2003, 2004, 2006; Wasik et al. 2007, 2010). This article reviews some important aspects concerning the chemistry, distribution, pharmacology, and mechanism of action of TIQ and its methyl derivative, 1MeTIQ the simplest representatives of the unsubstituted non-catechol tetrahydroisoquinolines in the mammalian brain. Synthesis of 1MeTIQ in the Brain 1MeTIQ was identified in normal rat brains by Kohno and coworkers (Kohno et al. 1986), and subsequently found to be present in foods rich in 2-phenylethylamine, which readily penetrates into the brain across the bloodbrain barrier (Makino et al. 1988). 1MeTIQ may be also synthesized enzymatically in the brain (Niwa et al. 1990). The enzyme involved in that process called 1MeTIQase was localized in the mitochondrial-synaptosomal fraction of rat brain, isolated, and purified (Niwa et al. 1990; Tasaki et al. 1993). Its activity is spread throughout the brain, the highest activity being observed in the dopaminergic areas that are implicated in the etiology of (...truncated)