Pharmacological evaluation of two novel analogues of mianserin: 2-N-carboxamidinonormianserin (FCC5) and 2-N-carboxamidonormianserin (FCC13).
1. The pharmacological properties have been examined of FCC5 (2-N-carboxamidinonormianserin) and FCC13 (2-N-carboxamidonormianserin), two novel analogues of mianserin. 2. FCC5 or FCC13 (100 micrograms/kg, i.v.) caused long-lasting (greater than 1 h) abolition of 5-hydroxytryptamine (5-HT) and histamine-induced bronchoconstriction in the anaesthetized guinea-pig. Both analogues had no effect (up to 1 mg/kg, i.v.) on bronchoconstriction caused by acetylcholine (25-50 micrograms/kg, i.v.). 3. The pressor effects of 5-HT in pithed rats were significantly attenuated by FCC5 (0.1 mg/kg, i.v.) or FCC13 (0.5 mg/kg, i.v.). 4. Oedema in the rat hind paw caused by intraplantar 5-HT was inhibited by FCC5 (ID50 0.76 mg/kg, i.p.; 2.7 mg/kg, p.o.) or FCC13 (ID50 0.65 mg/kg, i.p.; 5.8 mg/kg, p.o.). 5. In the central nervous system (CNS), FCC13 caused antagonism of 5-HT activity. It inhibited: (i) L-5-hydroxytryptophan (L-5-HTP)-induced head twitches in mice (ID50 1.85 mg/kg, i.p.), (ii) fenfluramine-induced facilitation of flexor reflex activity (FRA) in spinalized decerebrate rats (SDR) (IC50 0.57 mg/kg, i.p.). 6. FCC5 (less than or equal to 30 mg/kg, i.p. and less than or equal to 3 mg/kg, i.p., respectively) had no effect in either test. In contrast to mianserin, it also had no overt central actions as (less than or equal to 30 mg/kg, i.p.) had no effect on: (i) morphine-induced catalepsy (MIC) or (ii) clonidine-induced facilitation of FRA in SDR. However, high doses of FCC13 inhibited MIC (ID50 20 mg/kg, i.p.), but had no effect on (ii) (less than or equal to 10 mg/kg, i.p.). 7. Thus, FCC5 and FCC13 are potent, orally active H1 and 5-HT receptor antagonists. However, in contrast to FCC13 and mianserin, FCC5 did not cause CNS-mediated effects.
Department of Pharmacology, Monash University, Melbourne, Victoria, Australia.
I M
IM
Leitch
A
A
Rawlow
M P
MP
Rechtman
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D002490:Central Nervous System / Q000187:drug effects*; D003655:Decerebrate State; D004487:Edema / Q000139:chemically induced; D005260:Female; D005277:Fenfluramine / Q000494:pharmacology; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012018:Reflex / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*
D006634:Histamine H1 Antagonists; D012702:Serotonin Antagonists; C075500:FCC13; C075499:2-N-carboxamidinonormianserin; D008803:Mianserin; D005277:Fenfluramine; D012701:Serotonin; D009020:Morphine