Pharmacology Biochemistry & Behavior, Vol. 38, pp. 555-559. © Pergamon Press plc, 1991. Printed in the U.S.A.
0091-3057/91 $3.00 + .00
Characterization of a Novel and Potent 5-Hydroxytryptamine 1A Receptor Antagonist LINDA M. LIAU,* A N D R E W J. SLEIGHT,* JOSEF P I T H A t AND STEPHEN J. P E R O U T K A .1
*Department of Neurology, Stanford University Medical Center, Stanford, CA 94305 ~National Institutes of Health, National Institute on Aging/GRS, Baltimore, MD 21224 Received 9 April 1990
LIAU, L. M., A. J. SLEIGHT, J. PITHA AND S. J. PEROUTKA. Characterizationof a novelandpotent 5-hydroxytryptaminelA receptor antagonist. PHARMACOLBIOCHEM BEHAV 38(3) 555-559, 1991.--A series of pindolol derivatives(n=7) was analyzed in radioligandbinding, biochemicaland behavioral studies. Three of these drugs (Compounds A, B, and C) are extremely potent (i.e., Ki values < 1.0 nM) at 5-hydroxytryptarninelA(5-HTIA)sites labeled by [3HI 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Moreover, these drugs are selective in that they are approximatelyan order of magnitudeless potent at beta-adrenergic receptors labeled by 3H-dihydroalprenolol(DHA). Compound A (Nl-(bromoacetyl)-NS-[3-(4-indolyloxy)-2-hydroxypropyl] (Z)-l,8-diamino-p-methane)is also significantly less potent at 10 other neurotransmitterreceptor sites analyzed. In addition, Compound A (10 -1° M to 10-3 M) has no effect on baseline forskolin-stimulatedadenylatecyelase activity in rat hippocampos. By contrast, nanomolarconcentrationsof the drug significantly(p,
9o
c
3H-8-OH-DPAT 3H-5-HT 3H-Mesulergine 3H-5-HT 3H-Spiperone 3H-Quipazine
0.71 1300 33000 300 9400 4300
+-0.01 _ 100 +__ 3000 _ 100 _+ 100 +_ 200
3H-WB-4101 3H-Rauwolscine aH-DHA
6700 460 6.7
_ 500 ___ 200 --0.7
3H-SCH 23390 3H-Spiperone
83000 3700
___ 5000 ___ 900
> 100,000
aH-QNB
Radioligand binding assays were performed using rat membranes as described in the Method section. Values shown are the means--standard errors of 3-5 experiments, each performed in triplicate. tested. As shown in Fig. 3, nanomolar concentrations of Compound A reverse the inhibition of the forskolin-induced stimulation caused by 8-OH-DPAT. The initial effects of such reversal are shown at concentrations as low as 10 - 9 M of Compound A. In the presence of micromolar amounts of Compound A, the inhibition produced by 8-OH-DPAT is completely reversed.
Behavioral Effects of Compound A There is no observable behavioral change in the rat following subcutaneous (SC) injection of either saline or Compound A (0.5 mg/kg). Both control and experimental animals received total scores of 0 to 1 in all of the 4 behavioral effects that were investigated (i.e., reciprocal forepaw treading, head weaving, straub
L_ ~ O- o
70
u_
0091-3057/91 $3.00 + .00
Characterization of a Novel and Potent 5-Hydroxytryptamine 1A Receptor Antagonist LINDA M. LIAU,* A N D R E W J. SLEIGHT,* JOSEF P I T H A t AND STEPHEN J. P E R O U T K A .1
*Department of Neurology, Stanford University Medical Center, Stanford, CA 94305 ~National Institutes of Health, National Institute on Aging/GRS, Baltimore, MD 21224 Received 9 April 1990
LIAU, L. M., A. J. SLEIGHT, J. PITHA AND S. J. PEROUTKA. Characterizationof a novelandpotent 5-hydroxytryptaminelA receptor antagonist. PHARMACOLBIOCHEM BEHAV 38(3) 555-559, 1991.--A series of pindolol derivatives(n=7) was analyzed in radioligandbinding, biochemicaland behavioral studies. Three of these drugs (Compounds A, B, and C) are extremely potent (i.e., Ki values < 1.0 nM) at 5-hydroxytryptarninelA(5-HTIA)sites labeled by [3HI 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Moreover, these drugs are selective in that they are approximatelyan order of magnitudeless potent at beta-adrenergic receptors labeled by 3H-dihydroalprenolol(DHA). Compound A (Nl-(bromoacetyl)-NS-[3-(4-indolyloxy)-2-hydroxypropyl] (Z)-l,8-diamino-p-methane)is also significantly less potent at 10 other neurotransmitterreceptor sites analyzed. In addition, Compound A (10 -1° M to 10-3 M) has no effect on baseline forskolin-stimulatedadenylatecyelase activity in rat hippocampos. By contrast, nanomolarconcentrationsof the drug significantly(p,
9o
c
3H-8-OH-DPAT 3H-5-HT 3H-Mesulergine 3H-5-HT 3H-Spiperone 3H-Quipazine
0.71 1300 33000 300 9400 4300
+-0.01 _ 100 +__ 3000 _ 100 _+ 100 +_ 200
3H-WB-4101 3H-Rauwolscine aH-DHA
6700 460 6.7
_ 500 ___ 200 --0.7
3H-SCH 23390 3H-Spiperone
83000 3700
___ 5000 ___ 900
> 100,000
aH-QNB
Radioligand binding assays were performed using rat membranes as described in the Method section. Values shown are the means--standard errors of 3-5 experiments, each performed in triplicate. tested. As shown in Fig. 3, nanomolar concentrations of Compound A reverse the inhibition of the forskolin-induced stimulation caused by 8-OH-DPAT. The initial effects of such reversal are shown at concentrations as low as 10 - 9 M of Compound A. In the presence of micromolar amounts of Compound A, the inhibition produced by 8-OH-DPAT is completely reversed.
Behavioral Effects of Compound A There is no observable behavioral change in the rat following subcutaneous (SC) injection of either saline or Compound A (0.5 mg/kg). Both control and experimental animals received total scores of 0 to 1 in all of the 4 behavioral effects that were investigated (i.e., reciprocal forepaw treading, head weaving, straub
L_ ~ O- o
70
u_
