Novel 1,2,3,4-tetrahydroisoquinolines with high affinity and selectivity for the dopamine D3 receptor

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 2, 1999, Pages 179-184

  Austin, Nigel E ^a   Avenell, Kim Y ^a   Boyfield, Izzy ^a   Branch, Clive L ^a   Coldwell, Martyn C ^a   Hadley, Michael S ^a   Jeffrey, Phillip ^a   Johns, Amanda ^a   Johnson, Christopher N ^a   Nash, David J ^a   Riley, Graham J ^a   Smith, Stephen A ^a   Stacey, Rachel C ^a   Stemp, Geoffrey ^a   Thewlis, Kevin M ^a   Vong, Antonio K K ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

3 INDOLYLPROPENAMIDE; DOPAMINE 2 RECEPTOR; DOPAMINE 3 RECEPTOR; DOPAMINE 3 RECEPTOR BLOCKING AGENT; NEUROLEPTIC AGENT; TETRAHYDROISOQUINOLINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; DOPAMINERGIC SYSTEM; DRUG CLEARANCE; DRUG PENETRATION; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; INTRAVENOUS DRUG ADMINISTRATION; NONHUMAN; PSYCHOPHARMACOLOGY; PSYCHOSIS; RAT;

ANIMALS; BRAIN; ISOQUINOLINES; MODELS, MOLECULAR; RATS; RECEPTORS, DOPAMINE D2; RECEPTORS, DOPAMINE D3;

ANIMALIA;

EID: 0033579921     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00699-4     Document Type: Article

References (8)

1. Sokoloff, P.; Giros, B.; Martres, M-P.; Bouthenet, M-L.; Schwartz, J-C. Nature 1990, 347, 146-151.
2. Schwartz, J-C.; Levesque, D.; Martres, M-P.; Sokoloff, P. Clin. Neuropharmacol. 1993, 16, 295-314.
3. Shafer, R.A.; Levant, B. Psychopharmacology 1998, 135, 1-16.
4. Boyfield, I.; Coldwell, M.C.; Hadley, M.S.; Johnson, C.N.; Riley, G.J.; Scott, E.E.; Stacey, R.; Stemp, G. Bioorg. Med. Chem. Lett. 1997, 7, 1995-1998.
5. 2 receptors, expressed in CHO cells. Functional activity of the compounds was determined in vitro using microphysiometry (for details see Boyfield, I.; Brown, T.H.; Coldwell, M.C.; Cooper, D.G.; Hadley, M.S.; Hagan, J.J.; Healy, M.A.; Johns, A.J.; King, R.J.; Middlemiss, D.N.; Nash, D.J.; Riley, G.J.; Scott, E.E.; Smith, S.A. and Stemp, G. J. Med. Chem., 1996, 39, 1946-1948.
6. CNS penetration at steady-state was investigated in the rat. Compounds were dissolved in 2% (v/v) DMSO in 5% (w/v) dextrose aq and administered at a constant infusion rate over 12 h at a target dose rate of 0.3 mg free base/kg/h. Blood samples were removed during the latter part of the infusion to confirm steady-state blood concentrations. Blood and brain samples were analysed by LC/MS/MS. Values for blood clearance (CLb) were determined according to the relationship CLb = infusion rate/steady-state blood concentration (Css).
7. 1H (free base): δ 1.65 (m, 4H), 2.51 (m, 2H), 2.69 (t, J = 7 Hz, 2H), 2.89 (t, J = 7 Hz, 2H), 3.45 (m, 2H), 3.58 (s, 2H), 6.35 (d, J = 16 Hz, 1H), 6.36 (m, 1H), 6.90 (d, J = 16 Hz, 1H), 7.00 (dd, J = 9, 2 Hz, 1H), 7.05 - 7.46 (m, 5H), 7.85 (m, 2H), 9.20 (br s 1H).
8. Arylpropenamides 24, 25 and 31 were conveniently prepared from commercially available arylpropenoic acids; 26 and 30 were prepared from known acids. The arylpropenoic acids required for compounds 27 - 29 were readily prepared by Heck reaction of the appropriate aryl bromide with ethyl acrylate, under standard conditions, followed by hydrolysis of the resulting ester.