The selective 5-HT1B receptor inverse agonist 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro- spiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289) potently blocks terminal 5-HT autoreceptor function both in vitro and in vivo.
5-HT1 receptors are members of the G-protein-coupled receptor superfamily and are negatively linked to adenylyl cyclase activity. The human 5-HT1B and 5-HT1D receptors (previously known as 5-HT1Dbeta and 5-HT1Dalpha, respectively), although encoded by two distinct genes, are structurally very similar. Pharmacologically, these two receptors have been differentiated using nonselective chemical tools such as ketanserin and ritanserin, but the absence of truly selective agents has meant that the precise function of the 5-HT1B and 5-HT1D receptors has not been defined. In this paper we describe how, using computational chemistry models as a guide, the nonselective 5-HT1B/5-HT1D receptor antagonist 4 was structurally modified to produce the selective 5-HT1B receptor inverse agonist 5, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6, 7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289). This compound is a potent antagonist of terminal 5-HT autoreceptor function both in vitro and in vivo.
Gaster
L M
LM
SmithKline Beecham Pharmaceuticals, Discovery Research, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, England.
Blaney
F E
FE
Davies
S
S
Duckworth
D M
DM
Ham
P
P
Jenkins
S
S
Jennings
A J
AJ
Joiner
G F
GF
King
F D
FD
Mulholland
K R
KR
Wyman
P A
PA
Hagan
J J
JJ
Hatcher
J
J
Jones
B J
BJ
Middlemiss
D N
DN
Price
G W
GW
Riley
G
G
Roberts
C
C
Routledge
C
C
Selkirk
J
J
Slade
P D
PD
D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D017660:Autoreceptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000633:toxicity; D008297:Male; D008958:Models, Molecular; D010069:Oxadiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010881:Piperidones / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine
D017660:Autoreceptors; C470302:HTR1B protein, human; D007211:Indoles; D010069:Oxadiazoles; D010879:Piperazines; D010881:Piperidones; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; C108518:SB 22489G; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013141:Spiro Compounds; C108517:SKF 99101H; C090701:GR 127935; D001224:Aspartic Acid