SIGMA-LIGANDS WITH SUBNANOMOLAR AFFINITY AND PREFERENCE FOR THE SIGMA(2) BINDING-SITE .1. 3-(OMEGA-AMINOALKYL)-1H-INDOLES

• Published in: Journal of medicinal chemistry Vol. 38; no. 11; pp. 1998 - 2008
• Main Authors: PERREGAARD, J, MOLTZEN, EK, MEIER, E, SANCHEZ, C
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 26.05.1995
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; ANTAGONIST; 5-HT1A RECEPTOR; RAT; HALOPERIDOL; BMY-14802; INVITRO; DOPAMINE; MODEL; GUINEA-PIG BRAIN; POTENTIAL ANTIPSYCHOTIC AGENT
• ISSN: 0022-2623
• DOI: 10.1021/jm00011a019

A series of 4-(1H-indol-3-yl)-1-butyl-substituted 4-phenylpiperidines, 4-phenyl-1,2,3,6-tetra-hydropyridines, and 4-phenylpiperazines was synthesized. The phenyl group was optionally substituted with 4-fluoro or 2-methoxy substituents. High affinity for both sigma(1) and sigma(2) binding sites was achieved with these compounds. Additionally, these compounds had relatively high affinity for serotonin 5-HT1A and 5-HT2A, dopamine D-2, and adrenergic alpha(1) receptors. Introduction of a 4-fluorophenyl substituent at the indole nitrogen atom rendered very selective sigma(2) ligands with subnanomolar affinity for the sigma(2) binding site. The prototype of such a compound was 1-(4-fluorophenyl)-3-[4-[4-(4-fluorophenyl)-1-piperidinyl]-1-butyl]-1H-indole, 11a (code no. Lu 29-253). This compound had the following binding affinities: IC50 (sigma(1)) = 16 nM, IC50 (sigma(2)) = 0.27 nM, IC50 (5-HT1A)= 22 000 nM, IC50 (5-HT2A) = 270 nM, IC50 (D)(2) = 4200 nM, IC50 (alpha(1))= 220 nM. Spiro-joining of the phenyl and the piperidine rings into a spiro[isobenzofuran-1(3H),4'-piperidine] ring system resulted in even more selective compounds. Variations of the l-substituent at the indole and of the chain length of the alkylene spacer group were;studied. The optimal compound was the spiro analogue of compound 11a. This compound is 1'-[4-[1-(4-fluorophenyl)- 1H-indol-3-yl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine], 14f(code no. Lu 28-179), with the binding affinities: IC50(sigma(1)) = 17 nM, IC50 (sigma(2)) = 0.12 nM, IC50 (5-HT1A) = 21 000 nM, IC50 (5-HT2A) = 2000 nM, IC50 (D-2)= 800 nM, IC50 (alpha(1))= 330 nM. However, the most selective sigma(2) versus sigma(1) ligand was the tropane derivative 1-(4-fluorophenyl)-3-[4-[3-(4-fluorophenyl)-8-azabicyclo[3.2.l]oct-2-en-8-yl]-1-butyl]-1H-indole, 15a. This compound had the following binding affinitites: IC50 (sigma(1)) = 1200 nM, IC50 (sigma(2)) = 2.5 nM. Potent anxiolytic activity in the black/white box exploration test in rats was found with the two most prominent sigma(2) ligands Lu 29-253 and Lu 28-179. Good penetration into the CNS was documented both after subcutaneous and peroral administration of Lu 28-179 by ex vivo binding studies. Long duration of action was demonstrated both in ex vivo binding (T-1/2 similar to 20 h) and in the black/white box exploration test.