The subtypes of alpha1-adrenoceptor mediating facilitation of alpha-motoneuron activity in adult rat spinal cord were examined. The potencies of agonists and antagonists were compared, using extracellular single unit recordings made in spinal cord slices isolated from adult rats. Catecholamines (epinephrine, norepinephrine), phenylethylamines (phenylephrine, methoxamine) and imidazolines (clonidine, oxymetazoline, St587 (2-(2-chloro-5-trifluoromethyl-phenylimino)-imidazoline)) enhanced motoneuron activity. Catecholamines and phenylethylamines elicited maximal responses but imidazolines elicited submaximal responses. The potencies of the agonists were similar to their affinities for alpha1A-adrenoceptors. The alpha1A-adrenoceptor agonist SDZ NVI 085 ((-)-(4aR,10aR)-3,4,4a,5,10,10a-hexahydro-6-methoxy-4-methyl-9-methylthio-2H-naphth[2,3b]-1,4-oxazine) behaved as a partial agonist with a maximal response of about 75% and this response was not inhibited by chloroethylclonidine. Pretreatment with chloroethylclonidine produced a rightward shift of the phenylephrine response curve but caused little reduction in the maximal response. Prazosin, 5-methyl-urapidil, WB4101 (2-([2,6-dimethoxyphenoxyethyl] aminomethyl)-1,4-benzodioxane) and BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8azaspiro[4.5]decane-7,9-dione dihydrochloride) concentration dependently inhibited the facilitation of alpha-motoneuron activity produced by phenylephrine. The order of inhibitory potency was similar to that for their alpha1A-adrenoceptor binding site affinity. Therefore, it seems that alpha1A-adrenoceptors may be functionally predominant in the facilitation of rat spinal motoneuron activity.

01 Aug 1996·Journal of Autonomic Pharmacology

Characterization of α‐adrenoceptor subtype(s) mediating vasoconstriction in the perfused rabbit ovarian vascular bed

Article

Author: M. A. Oriowo ; K. I. Williams ; M. Yousif

1. alpha 1-Adrenoceptor agonists, noradrenaline, phenylephrine, methoxamine, oxymetazoline and SDZ NVI 085 but not alpha 2-adrenoceptor agonists, UK 14304, tizanidine or clonidine evoked dose-dependent vasoconstriction of the isolated perfused rabbit ovarian vascular bed. The rank order of agonist potency was noradenaline > oxymetazoline > phenylephrine > SDZ NVI 085 > methoxamine. 2. Prazosin (10(-8) M - 10(-5) M) displaced agonist dose-response curves to the right. The pA2/pKB values ranged between 7.27 and 7.66 against noradrenaline, phenylephrine, methoxamine and SDZ NVI 085 and were not significantly different from each other. Prazosin was however significantly less potent against oxymetazoline (pA2 6.38). Yohimbine (10(-6) M - 10(-5) M) was not very effective against any of the agonists. 3. WB 4101 (10(-8) M - 10(-5) M) displaced agonist dose-response curves to the right. The pA2/ pKB values ranged between 7.08 and 7.93 against noradrenaline, phenylephrine, methoxamine and SDZ NVI 085. WB 4101 was significantly less potent against oxymetazoline (pKB 6.85). 4. SZL-49 (5 x 10(-6) M) but not chloroethylclonidine (3 x 10(-5) M) significantly reduced vasoconstrictor responses to all the agonists. 5. Electrical field stimulation of the ovarian bed produced frequency-dependent vasoconstrictor effects which were abolished by 6-OHDA. The responses were also antagonized in a concentration-dependent by prazosin (10(-7) M - 10(-5) M) and WB 4101 (3 x 10(-8) M - 3 x 10(-7) M). Yohimbine reduced the response to electrical stimulation by 20% at 10(-5) M. The vasoconstrictor effect was also inhibited by SZL-49 but not by chloroethylclonidine. 6. These results would suggest that the vasoconstrictor responses of the ovarian vascular bed to adrenergic agonists and to electrical stimulation are mediated via the alpha 1A-adrenoceptor subtype.

01 Jul 1996·British Journal of PharmacologyQ2 · MEDICINE

Rat pineal α₁‐adrenoceptor subtypes: studies using radioligand binding and reverse transcription‐polymerase chain reaction analysis

Q2 · MEDICINE

Article

Author: Klein, David C. ; Anwar, Naveed ; Sugden, David

1. The pharmacological characteristics of alpha 1-adrenoceptor binding sites in rat pineal gland membranes, detected by use of a selective alpha 1-adrenoceptor antagonist ([125I]-iodo-2-[beta-(4-hydroxyphenyl) ethylaminomethyl]tetralone, [125I]-HEAT), were investigated with the alkylating agent, chloroethylclonidine (CEC), and in competition experiments with a number of adrenoceptor agonists and antagonists. 2. Chloroethylclonidine (CEC) treatment (10 microM, 10 min) of rat pineal membranes inactivated approximately 70% of specific [125I]-HEAT binding sites. Higher concentrations of CEC (up to 100 microM) or longer treatment periods (up to 40 min) were no more effective. 3. Adrenoceptor agonists and antagonists competitively inhibited [125I]-HEAT binding with Hill coefficients close to unity indicating a single alpha 1-adrenoceptor subtype is present. The affinity (Ki) of subtype selective agonists (oxymetazoline, SDZ NVI-085) and antagonists (5-methylurapidil, WB4101, benoxathian, phentolamine) was consistent with binding to an alpha 1B-adrenoceptor subtype. 4. The (-)- and (+)-enantiomers of niguldipine had an equal and low affinity for alpha 1-adrenoceptor binding sites both in untreated (log Ki-6.66 and -6.90 respectively) and CEC-treated membranes in which approximately 70% of sites had been inactivated (log Ki-6.41 and -6.86 respectively). This indicates that the small proportion of alpha 1-adrenoceptors insensitive to CEC are not alpha 1A-adrenoceptors. 5. mRNA was isolated from rat pinealocytes, cDNA was synthesized and then amplified by the polymerase chain reaction with alpha 1-adrenoceptor subtype specific primers. These experiments identified both alpha 1A- and alpha 1B-adrenoceptor mRNA, but not alpha 1D-mRNA in rat pinealocytes, although all three adrenoceptor subtypes were readily identified in rat brain cortex. 6. These data indicate that although both alpha 1A- and alpha 1B-adrenoceptor mRNAs are present in the pineal the major subtype of alpha 1-adrenoceptor expressed is the alpha 1B.

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Indication	Highest Phase	Country/Location	Organization	Date
Cognition Disorders	Phase 1	-	Novartis Pharma AG	-
Cognition Disorders	Phase 1	CH	Novartis AG	-
Depressive Disorder, Major	Phase 1	-	Novartis Pharma AG	-
Depressive Disorder, Major	Phase 1	CH	Novartis AG	-

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