5'-Thiodenosine Derivatives as Potent and Selective Inhibitors of Histamine N-Methyl-Transferase

Abstract

Several new analogues of adenosine bearing a lipophilic side chain at the 5'-position have been synthesized and investigated for their ability to inhibit histamine N-methyltransferase (HNMT). The 5'-deoxy-5'-[4-(3-indolyl)but-l-yl] thio}adenosine (2e), exhibited a pl 50 of 5.00 against guinea pig brain HNMT. Interestingly, the polar methyl sulphonium analogue (7c) was a more potent inhibitor of this enzyme (pl 50 =5.26). Both compounds were relatively ineffective inhibitors of rabbit adrenal phenylethanolamine N-methyltransferase (PNMT), rabbit lung indoleamine N-methyltransferase (INMT), and rat brain catechol O-methyltransferase (COMT). 5 -[N(4-phenylbutyl)] -amino-5 cieoxyadenosine (2a) and 5 -[N-methyl,N-(4-phenylbutyl] -amino-5 cleoxyadenosine (2b) also exhibited potent and selective inhibition against guinea pig brain HNMT. Results from kinetic studies indicate that the above compounds are inhibitors that compete for both the histamine and the S-adenosylmethionine (SAM) binding sites of HNMT. Compound lc is one of the most potent adenosine analogue inhibitors of HNMT known. Fig. 1: The histamine N-methyltransferase-catalyzed reaction.

Structure-Based Drug Design of Bisubstrate Inhibitors of Phenylethanolamine N-Methyltransferase Possessing Low Nanomolar Affinity at Both Substrate Binding Domains1

“…The solvent was removed under reduced pressure and the residue was purified by chromatography on a silica gel column eluting with CHCl 3 /MeOH (30:1) to yield yellow foam (1.70 g), which was purified by the reported procedures to afford regiopure 40. 75 Journal of Medicinal Chemistry (±)-1,1-Dimethylethyl 3,4-Dihydro-3-(N-methoxy-N-methylcarbamoyl)-isoquinoline-2(1H)-carboxylate (42). 78 Weinreb amide 42 was prepared by following the literature procedure.…”

“…The bisubstrate analogue approach has been applied to develop inhibitors for other AdoMet-dependent methyltransferases. − Most relevant among these is the 2.6 Å resolution crystal structure of a bisubstrate inhibitor ( 8 , Figure ) complexed with catechol O -methyltransferase (COMT) that showed good inhibitory potency (IC 50 = 9 nM), as compared to entacapone ( 9 ), a clinically used inhibitor of COMT (IC 50 = 14 nM) …”

Ανοσοφαρμακολογική Διερεύνηση Της Αλληλεπίδρασης Ισταμίνης Και Κυτοκινών Σε Φυσιολογικές Και Παθολογικές Καταστάσεις

“…Στον Πίνακα 1.1 συνοψίζονται οι κυριότεροι αναστολείς της HDC και της HNMT (Futo et al 1988, Crooks et al 1990, Cumming et al 1990, Futo et al 1990, Watanabe et al 1990, Jochem et al 2002. (Gurish and Austen 2001).…”

Μελέτη Του Νευροανοσοφαρμακολογικού Ρόλου Της Ισταμίνης Στον Υποθάλαμο

“…Έχει επίσης καταδειχθεί ότι ένα µικρό ποσοστό ισταµίνης µπορεί να οξειδωθεί υπό την επίδραση µιας µη ειδικής διαµινοξειδάσης σε ιµιδαζολοξικό οξύ, το οποίο έχει ιδιότητες αγωνιστή των υποδοχέων του γ-αµινοβουτυρικού οξέος (GABA) (Thomas and Prell 1995). Στον Πίνακα 1.1 συνοψίζονται οι κυριότεροι αναστολείς της HDC και της HNMT (Futo et al 1988, Crooks et al 1990, Cumming et al 1990, Futo et al 1990, Cumming et al 1992, Jochem et al 2002 Leurs et al 1995, Schneider et al 2002, Jablonowski et al 2004.…”