Lack of stereoselectivity of 8-hydroxy-2(di-N-propylamino)tetralin-mediated inhibition of forskolin-stimulated adenylyl cyclase activity in human pre- and post-synaptic brain regions.
The stereoselectivity of the serotonin1A (5-HT1A) receptor compound 8-hydroxy-2(di-N-propylamino)tetralin (8-OH-DPAT) on forskolin-stimulated adenylyl cyclase activity was investigated in membranes from human 5-HT pre-synaptic (raphe nuclei) and post-synaptic (hippocampus and prefrontal cortex) regions of autopsy brains. After sample incubation with agonists and antagonists, results showed that both the racemic mixture of 8-OH-DPAT or its (+) and (-) enantiomers behaved as full agonists in the tested brain regions. Enantiomer potency (EC50, nM) and efficacy (percentage of maximal inhibition, %) values were similar in all regions under investigation. However, some inter and intra-region variations in racemic 8-OH-DPAT potency and efficacy have been observed. In particular, the potency of racemic 8-OH-DPAT was higher in the prefrontal cortex and raphe nuclei than in the hippocampus, where it was in fact lower than either single enantiomers. Agonist effects were competitively reversed by 5-HT1A antagonists, although once again a different profile was revealed in the hippocampus. The data underscores the lack of stereospecificity of 8-OH-DPAT-mediated inhibition of adenylyl cyclase activity in either pre- or post-synaptic human brain regions. Moreover, such results have significant implication, as they support the notion that human 5-HT1A receptors might vary from one brain region to the other.
Palego
L
L
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, Italy. liopal@yahoo.com
Giromella
A
A
Marazziti
D
D
Giannaccini
G
G
Borsini
F
F
Bigazzi
F
F
Naccarato
A G
AG
Lucacchini
A
A
Cassano
G B
GB
Mazzoni
M R
MR
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000737:chemistry / Q000494:pharmacology*; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D005576:Colforsin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000187:drug effects / Q000201:enzymology; D017729:Presynaptic Terminals / Q000201:enzymology; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013569:Synapses / Q000201:enzymology*
D000067956:Adenylyl Cyclase Inhibitors; D004791:Enzyme Inhibitors; D017366:Serotonin Receptor Agonists; D005576:Colforsin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000262:Adenylyl Cyclases