Nature-inspired indolyl-2-azabicyclo[2.2.2]oct-7-ene derivatives as promising agents for the attenuation of withdrawal symptoms: synthesis of 20-desethyl-20-hydroxymethyl-11-demethoxyibogaine.
Microwave assisted Diels-Alder cycloaddition of 5-Br-N-benzylpyridinone (2) with methyl acrylate is described to gain an easy access to 7-bromo-2-benzyl-3-oxo-2-aza-5 or 6-carbomethoxy bicyclo[2.2.2]oct-7-enes (3)-(6). The preparation of the ibogaine analogue 20-desethyl-(20-endo)-hydroxymethyl-11-demethoxyibogaine (17) is described by stereoselective hydrogenation of the C(7)-C(8) double bond. Biological evaluation showed an interesting in vitro binding profile toward dopamine transporter, serotonin transporter and opioid receptor systems accompanied by an antiwithdrawal effect in mice for hydroxymethyl 7-indolyl-2-aza-bicyclo[2.2.2]oct-2-ene (14). The simplification of the ibogaine structure appears as a promising approach toward the design of compounds that could reduce the withdrawal symptoms.
Passarella
D
D
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Via Venezian, 21-20133 Milano, Italy. daniele.passarella@unimi.it
Barilli
A
A
Efange
S M N
SM
Elisabetsky
E
E
Leal
M B
MB
Lesma
G
G
Linck
V M
VM
Mash
D C
DC
Martinelli
M
M
Peretto
I
I
Silvani
A
A
Danieli
B
B
D000818:Animals; D007050:Ibogaine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D008297:Male; D051379:Mice; D015394:Molecular Structure; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*
C513845:20-desethyl-20-hydroxymethyl-11-demethoxyibogaine; D007050:Ibogaine