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Vol. 290, Issue 3, 1258-1269, September 1999
Pharmaceutical Research and Development Division, Recordati
S.p.A., Milan, Italy
Several novel N-arylpiperazine derivatives
were synthesized and tested for their 1) affinity and functional
activity on 5-hydroxytryptamine1A (5-HT1A)
receptors in vitro; 2) activity in models predictive of antagonism at
somatodendritic and postsynaptic 5-HT1A receptors; and 3)
effects on the micturition reflex in anesthetized and conscious rats.
These studies also included
1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine
hydrobromide (NAN 190),
8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione dihydrochloride (BMY 7378), and
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl-N-(2-pyridinyl)cyclohexanecarboxamide (WAY 100635). Almost all compounds were found to be potent and selective for the human recombinant 5-HT1A receptor, with
Ki values in the nanomolar range.
[35S]GTP
S binding in HeLa cells expressing the
recombinant human 5-HT1A receptor allowed classification of
the compounds into neutral antagonists and partial agonists. Almost all
neutral antagonists were active in blocking
8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT)-induced forepaw treading
in rats (postsynaptic model) and hypothermia in mice (somatodendritic
model) with the same potency, whereas compounds showing partial
agonistic activity were active in the postsynaptic model but were
inactive, or poorly active, in the somatodendritic model. Neutral
antagonists potently inhibited volume-induced bladder-voiding
contractions in anesthetized rats. Contractions were completely
blocked, and the disappearance of bladder contractions lasted 7 to 13 min after the highest doses tested. Furthermore, neutral antagonists
increased bladder volume capacity in conscious rats during
continuous transvesical cystometry, whereas micturition pressure was
only slightly, and not dose-dependently, reduced. Partial agonists were
inactive or poorly active, inducing a disappearance time of bladder
contractions that did not exceed 6 min in anesthetized rats, and
failing to increase bladder volume capacity in conscious rats. These
findings indicate that only neutral 5-HT1A receptor
antagonists are endowed with inhibitory effects on the bladder.
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