5-HT1D SEROTONIN RECEPTORS - RESULTS OF A STRUCTURE-AFFINITY INVESTIGATION

被引:36
作者
GLENNON, RA [1 ]
ISMAIEL, AM [1 ]
CHAURASIA, C [1 ]
TITELER, M [1 ]
机构
[1] UNION UNIV,DEPT PHARMACOL & TOXICOL,ALBANY,NY 12208
关键词
STRUCTURE-ACTIVITY; MEDICINAL CHEMISTRY; RECEPTOR AFFINITY;
D O I
10.1002/ddr.430220103
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
As a prelude to the design of 5-HT1D agents, we systematically investigated the structure-affinity relationships for the binding of indolealkylamines and related derivatives at 5-HT1D serotonin receptors. The results of the investigation reveal that a) methylation of a 5-hydroxyl group decreases affinity by 2-fold, b) replacement of a 5-hydroxyl group by hydrogen reduces affinity by an order of magnitude, c) alpha-methylation of the side chain reduces affinity by approximately 50-fold, d) N,N-dimethylation decreases affinity by 4-fold, e) methylation at the 2-position reduces affinity by 300-fold, f) small alkyl substituents are not well tolerated at the C7- and N1-positions, g) shortening of the side chain by one methylene unit reduces affinity by two orders of magnitude, h) cyclization of the side chain to a beta-carboline dramatically reduces affinity, and i) the 5-hydroxy group can be replaced by a carboxamido, benzyloxy, or chlorobenzyloxy moiety without any decrease in affinity. These studies led to the evaluation of certain non-indolealkylamines and to the finding that a) simple phenylalkylamines and phenylpiperazines bind with low affinity, but that their benz-fused counterparts bind with significantly higher affinity, and b) the 7-methoxy analog of 1-(1-naphthyl)piperazine (7-OMe 1-NP) binds at 5-HT1D sites with an affinity (Ki = 2 nM) comparable to that of serotonin itself. Various leads were developed that might aid the subsequent design of 5-HT1D-selective agents.
引用
收藏
页码:25 / 36
页数:12
相关论文
共 21 条
  • [1] PROPOSALS FOR THE CLASSIFICATION AND NOMENCLATURE OF FUNCTIONAL RECEPTORS FOR 5-HYDROXYTRYPTAMINE
    BRADLEY, PB
    ENGEL, G
    FENIUK, W
    FOZARD, JR
    HUMPHREY, PPA
    MIDDLEMISS, DN
    MYLECHARANE, EJ
    RICHARDSON, BP
    SAXENA, PR
    [J]. NEUROPHARMACOLOGY, 1986, 25 (06) : 563 - 576
  • [2] (R)-(-)-10-METHYL-11-HYDROXYAPORPHINE - A HIGHLY SELECTIVE SEROTONERGIC AGONIST
    CANNON, JG
    MOHAN, P
    BOJARSKI, J
    LONG, JP
    BHATNAGAR, RK
    LEONARD, PA
    FLYNN, JR
    CHATTERJEE, TK
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1988, 31 (02) : 313 - 318
  • [3] 5-HT1A-RECEPTOR ANTAGONISM - N-ALKYL DERIVATIVES OF (R)-(-)-8,11-DIMETHOXYNORAPORPHINE
    CANNON, JG
    JACKSON, H
    LONG, JP
    LEONARD, P
    BHATNAGAR, RK
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1989, 32 (08) : 1959 - 1962
  • [4] N-(PHTHALIMIDOALKYL) DERIVATIVES OF SEROTONERGIC AGENTS - A COMMON INTERACTION AT 5-HT1A SEROTONIN BINDING-SITES
    GLENNON, RA
    NAIMAN, NA
    PIERSON, ME
    SMITH, JD
    ISMAIEL, AM
    TITELER, M
    LYON, RA
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1989, 32 (08) : 1921 - 1926
  • [5] GLENNON RA, 1990, IN PRESS SEROTONIN R
  • [6] DETECTION AND CHARACTERIZATION OF A 5HT1D SEROTONIN RECEPTOR-GTP BINDING-PROTEIN INTERACTION IN PORCINE AND BOVINE BRAIN
    HERRICKDAVIS, K
    TITELER, M
    [J]. SYNAPSE, 1989, 3 (04) : 325 - 330
  • [7] DETECTION AND CHARACTERIZATION OF THE SEROTONIN 5-HT1D RECEPTOR IN RAT AND HUMAN-BRAIN
    HERRICKDAVIS, K
    TITELER, M
    [J]. JOURNAL OF NEUROCHEMISTRY, 1988, 50 (05) : 1624 - 1631
  • [8] SEROTONIN 5-HT1D RECEPTORS IN HUMAN PREFRONTAL CORTEX AND CAUDATE - INTERACTION WITH A GTP BINDING-PROTEIN
    HERRICKDAVIS, K
    TITELER, M
    LEONHARDT, S
    STRUBLE, R
    PRICE, D
    [J]. JOURNAL OF NEUROCHEMISTRY, 1988, 51 (06) : 1906 - 1912
  • [9] HEURING RE, 1987, J NEUROSCI, V7, P894
  • [10] LOWRY OH, 1951, J BIOL CHEM, V193, P265