Abstract
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), andN-[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, withKi values in the nanomolar range. [35S]GTPγS 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.
Footnotes
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Send reprint requests to: Rodolfo Testa, Pharmaceutical R&D Division, RECORDATI S.p.A., Via Civitali 1, 20148 Milan, Italy. E-mail:TESTA.R{at}RECORDATI.it
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↵1 Some of these data have already been presented in abstract form (Testa et al., 1998a; Guarneri et al., 1998).
- Abbreviations:
- 5-HT
- 5-hydroxytryptamine (serotonin)
- CHO
- Chinese hamster ovary
- NRM
- nucleus raphe magnum
- VIVC
- volume-induced bladder-voiding contractions
- DT
- disappearance time
- BVC
- bladder volume capacity
- MP
- micturition pressure
- Received January 29, 1999.
- Accepted May 5, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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