Studies toward the discovery of the next generation of antidepressants. 3. Dual 5-HT1A and serotonin transporter affinity within a class of N-aryloxyethylindolylalkylamines.
N-aryloxylethylindolealkylamines (5) having dual 5-HT transporter and 5-HT(1A) affinity are described. These compounds represent truncated analogues of our previously reported piperidinyl derivatives (3). Compounds in this investigation were found to have more similar affinities and functional activities for the 5-HT(1A) receptor and 5-HT transporter. Though 5-HT(1A) antagonism is not consistently observed throughout series 5, several molecular features were found to be essential to obtain high and balanced activities. The proper placement of a heteroatom in the aryl ring and the length of the linkage used to tether the indole moiety had significant influence on 5-HT(1A) and 5-HT transporter affinities. Introduction of a halogen into the aryl ring usually lowered intrinsic activity and in some cases led to full 5-HT(1A) antagonists. Compounds 33 and 34 were observed to be full 5-HT(1A) antagonists with K(i) values of approximately 30 nM for the 5-HT(1A) receptor and K(i) values of 5 and 0.5 nM for the 5-HT transporter, respectively. Unfortunately, similar to our previous series (3), compounds in this report also had high affinity for the alpha(1) receptor.
Mewshaw
Richard E
RE
Chemical and Screening Sciences and Neuroscience Discovery Research, Wyeth Research, P.O. Box 42528, Philadelphia, PA 19101-2528, USA. mewshar@wyeth.com
Zhou
Dahui
D
Zhou
Ping
P
Shi
Xiaojie
X
Hornby
Geoffrey
G
Spangler
Taylor
T
Scerni
Rosemary
R
Smith
Deborah
D
Schechter
Lee E
LE
Andree
Terrance H
TH
D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects* / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship
D000588:Amines; D000928:Antidepressive Agents; D002352:Carrier Proteins; D007211:Indoles; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018340:Receptors, Adrenergic, alpha-1; C493230:SLC6A4 protein, human; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C493232:Slc6a4 protein, rat; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin