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J R Fozard

Publications and source records attributed to J R Fozard.

At least 73 records · Page 4Linked to original sources
PubMed1988

Graphics computer-aided receptor mapping as a predictive tool for drug design: development of potent, selective, and stereospecific ligands for the 5-HT1A receptor.

A conformational study of four 5-HT1A (serotonin) receptor ligands ((R-(-)-methiothepin, spiperone, (S)-(-)-propranolol, and buspirone) led to the definition of a pharmacophore and a three-dimensional map of the 5-HT1A antagonist recognition site. These models were used to design new compounds and successfully predict their potency, stereospecificity, and selectivity. For example, 8-[4-[(1,4-benzodioxan-2-ylmethyl)amino] butyl]-8-azaspiro[4.5]decane-7,9-dione (1, MDL 72832) has nanomolar affinity (pIC50 = 9.14) for the 5-HT1A binding site in rat frontal cortex. As predicted, the S-(-) enantiomer of 1 was more active than its R-(+) enantiomer (pIC50 = 9.21 and 7.66, respectively) and a naphthalene analogue of 1 displayed the expected improved selectivity.

Animals↗
PubMed1988

Comparison between the cardiovascular effects of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and clonidine in the conscious sino-aortic denervated rat.

1. The purpose of this study was to investigate the role of an intact baroreceptor reflex mechanism in the expression of the cardiovascular response to 8-OH-DPAT and to determine whether there are any differences between the activation of central alpha 2-adrenoreceptors and 5-HT1A receptors in this respect. To this end, the effects of 8-OH-DPAT and clonidine have been assessed on blood pressure, heart rate, ECG and cardiac contractility indices in conscious sino-aortic baroreceptor denervated (SAD) rats and their sham-operated controls. 2. In both sham-operated and SAD rats, intravenous (i.v.) administration of 8-OH-DPAT (32 micrograms kg-1) and clonidine (8 micrograms kg-1) produced falls in systemic blood pressure, left ventricular systolic pressure and dP/dtmax. 3. 8-OH-DPAT produced similar bradycardia in each group of rats; in contrast, clonidine had a greater effect in the SAD animals. Increases of the PQ interval mirrored the heart-rate changes with both compounds. 4. No significant changes in end diastolic blood pressure or in the myocardial contractility indices dP/dtmax/P and Vmax were evident. 5. This study provides support for the view that i.v. 8-OH-DPAT lowers blood pressure and heart rate through a central mechanism. The effects occur independently of an intact baroreceptor reflex and are not associated with effects on myocardial contractility. 8-OH-DPAT shows close qualitative similarities to clonidine in this model.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Evidence that the putative 5-HT1A receptor agonists, 8-OH-DPAT and ipsapirone, have a central hypotensive action that differs from that of clonidine in anaesthetised cats.

Thoracic preganglionic sympathetic nerve activity, blood pressure, heart rate and femoral arterial conductance were recorded in anaesthetised, paralysed cats. Cumulative dose-response curves were constructed for 8-OH-DPAT, ipsapirone and clonidine. All three drugs caused dose-related falls in blood pressure which were associated with minimal changes in femoral arterial conductance. However, 8-OH-DPAT and ipsapirone differed from clonidine in that their hypotensive action was associated with moderate sympathoinhibition and a profound bradycardia, whereas clonidine caused profound sympathoinhibition and, as it did not increase central vagal tone, only a moderate bradycardia. 8-OH-DPAT also caused sympathoinhibition in bi-vagotomised cats and decreased carotid sinus nerve activity along with blood pressure. As 8-OH-DPAT and ipsapirone bind selectively to central 5-HT1A receptors it is concluded that central stimulation of these receptors causes sympathoinhibition and an increase in vagal tone, whereas stimulation of central alpha 2-adrenoceptors causes only sympathoinhibition. In addition, the present data suggest a peripheral vasodilator mechanism may also contribute to the hypotensive effects of 8-OH-DPAT and ipsapirone in the cat. The nature and relative importance of this remains to be established.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Mediation of the discriminative stimulus properties of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) by the putative 5-HT1A receptor.

Male Sprague-Dawley rats were trained to discriminate the putative 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) from saline in a 2-lever operant drug discrimination paradigm. The 8-OH-DPAT cue was found to be highly selective; neither the 5-HT receptor agonists, quipazine, LSD, MK 212 and RU 24969, the 5-HT releasing agent, p-chloroamphetamine, nor the alpha 2-adrenoceptor agonist, clonidine, were able to substitute for 8-OH-DPAT in tests of generalization. In contrast, both buspirone and TVX Q 7821, which like 8-OH-DPAT have high affinity and selectivity for the 5-HT1A recognition site, generalized to the 8-OH-DPAT cue in a dose-dependent manner. The discriminative stimulus properties of 8-OH-DPAT were not antagonized by the 5-HT2 receptor antagonist, ketanserin, or the selective beta 1- and beta 2-adrenoceptor antagonists, betaxolol and ICI 118.551, indicating that neither 5-HT2 receptors, nor beta-adrenoceptors play a significant role in the behaviour. However, the 8-OH-DPAT cue was antagonized stereoselectively by pindolol and alprenolol, which have relatively high affinity and stereoselectivity for 5-HT1, but not 5-HT2, recognition sites. Similarly, the capacity of TVX Q 7821 to generalize to the 8-OH-DPAT cue could be blocked by pindolol. In view of the fact that 8-OH-DPAT has negligible affinity for the 5-HT1B site, the above results are consistent with its discriminative stimulus properties being mediated by the putative 5-HT1A receptor. Moreover, agonist activity at central 5-HT1A receptors may be an important mechanism contributing to the anxiolytic properties of buspirone and TVX Q 7821.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Cardiovascular response to 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in the rat: site of action and pharmacological analysis.

The cardiovascular response to 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a selective putative 5-HT1A receptor agonist, has been investigated in the rat. Comparisons were made with clonidine, a centrally acting hypotensive agent with negligible affinity for 5-HT receptors. In conscious, spontaneously hypertensive (SH) rats, 8-OH-DPAT caused dose-related and sustained falls in blood pressure and heart rate that were unaffected by depletion of brain 5-HT by p-chlorophenylalanine. 8-OH-DPAT caused hypotension and bradycardia in anesthetized normotensive rats. In pithed rats, 8-OH-DPAT neither lowered blood pressure nor affected the cardiovascular response to spinal sympathetic stimulation or to phenylephrine. The response to 8-OH-DPAT was blocked selectively by intracisternal injection of 8-methoxy-2-(N-2-chloroethyl-N-n propyl) amino tetralin (8-MeO-CIEPAT), a putative irreversible 5-HT1A receptor antagonist, and was abolished in animals whose central monoamine transmitter stores were depleted selectively by combined treatment with DL-alpha-monofluoromethyl-dopa and dopamine. The cardiovascular response to 8-OH-DPAT was inhibited selectively by metergoline, methiothepin, and 8-MeO-CIEPAT; it was nonselectively inhibited by (+/-)-pindolol, (+/-)-cyanopindolol, buspirone, yohimbine, idazoxan, and WY 26392; and was unaffected by prazosin and cis-flupenthixol. These results establish that the cardiovascular response to 8-OH-DPAT in the rat is centrally mediated and point to the putative 5-HT1A receptor as the key site involved. An indirect link involving a catecholaminergic mechanism is suggested by the fact that alpha 2-adrenoceptor antagonists are also inhibitory despite 8-OH-DPAT having no direct agonist effects at alpha 2-adrenoceptors per se.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

Monoamine receptor sensitivity changes following chronic administration of MDL 72394, a site-directed inhibitor of monoamine oxidase.

(E)-beta-Fluoromethylene-m-tyrosine (MDL 72394) is not per se an inhibitor of monoamine oxidase (MAO) but is a substrate of aromatic L-amino acid decarboxylase (AADC) which liberates the potent MAO inhibitor (E)-beta-fluoromethylene-m-tyramine (MDL 72392). When co-administered to animals with the peripherally selective AADC inhibitor, carbidopa, MDL 72394 inhibited MAO selectively in the brain. Chronic (14 days plus 3 days withdrawal) administration of 0.5 mg/kg per day p.o. MDL 72394, 0.1 mg/kg per day p.o. MDL 72394 combined with 10 mg/kg per day p.o. carbidopa or 50 mg/kg per day p.o. pargyline produced equivalent inhibition of rat brain MAO and decreased the binding of [3H]clonidine and [3H]RX 781094 to the alpha 2-adrenoceptor and of [3H]dihydroalprenolol to the beta-adrenoceptor without changing binding of [3H]prazosin to the alpha 1-adrenoceptor. The locomotor depressant effect of clonidine was attenuated without attenuation of the hypotensive effect in rats treated chronically with the MAO inhibitors. Neither the sensitivity of the alpha 2-autoreceptor nor of the alpha 2-heteroreceptor was decreased in brain slices. However, the sensitivity of adenylate cyclase to activation by both noradrenaline and isoprenaline was significantly reduced. The number of 5-HT2 and 5-HT1A binding sites was decreased: the 5-HT1B binding sites remained unchanged. The effect of chronic MAO inhibitor treatment on 5-HT1A receptors was associated with a decrease in the behavioural response to 8-hydroxy-2-(di-n-propylamino)tetralin and the decrease in 5-HT2 binding was related to a small reduction in the sensitivity of the inositol phosphate system to stimulation by 5-HT. The lack of effect of chronic MAO treatment on the 5-HT autoreceptor measured in cortical slices corresponded to a lack of effect on the 5-HT1B binding site except that chronic administration of pargyline produced a small but significant decrease in 5-HT autoreceptor sensitivity. Overall, the data show that chronic administration of MDL 72394 has a profile of effects on central monoamine receptor binding and function similar to that seen following chronic administration of a number of clinically effective antidepressants.

Adenylyl Cyclases↗
PubMed1986

Blockade of the flare response to intradermal 5-hydroxytryptamine in man by MDL 72.222, a selective antagonist at neuronal 5-hydroxytryptamine receptors.

MDL 72.222 is a potent and selective antagonist of excitatory neuronal 5-hydroxytryptamine (5-HT) receptors which has been shown to provide symptomatic benefit in migraine. In the present study, the effects of MDL 72.222 on the flare response to intradermal injection of 5-HT (10(-5), 4 X 10(-5) and 1.6 X 10(-4) mol/l) have been examined in six healthy male volunteers using a double-blind, placebo-controlled, randomized, crossover design. The study consisted of two sessions separated by at least 5 days. Comparison of within and between day responses to 5-HT indicated good reproducibility. Significant attenuation of the flare response to 5-HT, 10(-5) and 4 X 10(-5) mol/l was observed following a slow (4 min) i.v. injection of MDL 72.222, 20 mg. No significant change was observed for the 1.6 X 10(-4) mol/l dose. The investigator was able to guess with a high degree of accuracy the sequence of MDL 72.222 and placebo (100% correct) and the order of 5-HT dose administration (70% correct), providing further evidence of the reproducibility and sensitivity of the method. MDL 72.222 was well tolerated. Thus, a dose of MDL 72.222 previously shown to provide symptomatic relief in migraine attenuates the flare response to intradermal 5-HT in the human forearm. The observation strengthens the view that the beneficial effects of MDL 72.222 in migraine result from blockade of the sensory neuronal stimulant effects of 5-HT and implies a role for 5-HT in the pain production of the acute attack.

Adult↗
PubMed1986

Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine.

As a result of controversy in the literature regarding the classification and nomenclature of functional receptors for 5-hydroxytryptamine (5-HT), a framework for classification is proposed. The formulation of these proposals has only been made possible by the recent advent of new drug tools. It is considered that there are three main types of 5-HT receptor, two of which have been well characterised pharmacologically, using selective antagonists, and which it is proposed to name 5-HT2 and 5-HT3. These two groups broadly encompass the "D" and "M" receptors, respectively, which Gaddum identified in the guinea-pig ileum (Gaddum and Picarelli, 1957). The 5-HT2 receptor, which mediates a variety of actions of 5-HT, has been definitively shown to correlate with the 5-HT2 binding site in the brain. No binding studies in brain tissue have yet been published with radiolabelled ligands specific for 5-HT3 receptors. A number of other actions of 5-HT appear to be mediated via receptors distinct from 5-HT2 or 5-HT3 receptors. Since selective antagonists are not yet available, these receptors cannot be definitively characterised, although in many cases they do have some similarities with 5-HT1 binding sites, which are a heterogeneous entity. Criteria are proposed for tentatively classifying these receptors as "5-HT1-like" (Table 1). Definitive characterisation of these receptors will await the identification of specific antagonists. This classification of 5-HT receptors into three main groups (Table 1) is based largely, but not exclusively, on data from studies in isolated peripheral tissues where definitive classification is possible. However, it is believed that this working classification will be relevant to functional responses to 5-HT in the central nervous system.

Animals↗
PubMed1986

Selective inhibition of monoamine oxidase type B by MDL 72145 increases the central effects of L-dopa without modifying its cardiovascular effects.

The potential of a new, potent, irreversible and selective inhibitor of monoamine oxidase type B, (E)-2-(3,4-dimethoxyphenyl)-3-fluorallyamine (MDL 72145), to augment the effects of L-DOPA in an animal model which reproduces the biochemical defect of Parkinson's disease has been evaluated. In rats bearing unilateral 6-hydroxydopamine lesions of the nigro-striatal dopamine pathways, both MDL 72145 and clorgyline, a selective inhibitor of MAO A, augmented the contralateral turning response to L-DOPA combined with carbidopa. The potential of inhibitors of MAO to interact adversely in the periphery with L-DOPA was investigated in the pithed rat; L-DOPA was given either intravenously or intraduodenally. Clorgyline consistently potentiated L-DOPA when given 18 h before testing. Neither MDL 72145 nor the selective inhibitor of MAO B, L-deprenyl, augmented the cardiovascular effects of intraduodenally administered L-DOPA. The data provide no reason to suppose that MDL 72145 would be very different in clinical use from L-deprenyl which is both effective and well-tolerated as an adjunct to the L-DOPA-based therapy of Parkinson's disease.

Allylamine↗
PubMed1985

Subtypes of the 5-HT receptor mediating the behavioural responses to 5-methoxy-N,N-dimethyltryptamine in the rat.

The 5-HT receptor subtypes involved in the mediation of reciprocal forepaw treading and the flat body posture induced by the central 5-HT receptor agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), were examined in intact rats and in rats depleted of monoamines with reserpine. Forepaw treading in non-reserpinised rats was antagonised by the 5-HT2 receptor antagonist, ketanserin, only at doses in excess of those required for occupation of a large proportion of 5-HT2 receptors in brain, and at which there was significant inhibition of stereotyped sniffing induced by the dopamine receptor agonist, apomorphine. Since forepaw treading induced by 5-MeODMT was also blocked in intact rats by haloperidol, blockade of the behaviour by ketanserin may more accurately reflect antagonism at dopamine receptors than at 5-HT2 receptors. In reserpinised rats, i.e. with minimised contributions from other monoamine systems, neither forepaw treading nor the flat body posture were significantly altered by ketanserin, haloperidol or the beta 1- and beta 2-selective adrenoceptor antagonists, betaxolol and ICI 118.551, making a key role for 5-HT2 receptors, dopamine receptors and beta-adrenoceptors unlikely. In contrast, forepaw treading in both reserpinised and non-reserpinised rats was antagonised stereoselectively by pindolol and by spiperone, which interact with 5-HT1 and 5-HT1A recognition sites. The results are consistent with the hypothesis that forepaw treading induced by 5-MeODMT arises by activation of the putative 5-HT1A receptor. Antagonism of the flat body posture by pindolol could be demonstrated only in non-reserpinised rats and the mechanism of induction of this behaviour remains to be established.

Animals↗
PubMed1985

The functional consequences of inhibition of monoamine oxidase type B: comparison of the pharmacological properties of L-deprenyl and MDL 72145.

The pharmacological properties of two selective inhibitors of monoamine oxidase (MAO) type B, L-deprenyl and MDL 72145 [(E)-2-(3,4-dimethoxyphenyl)-3-fluoroallylamine, HCl], have been investigated in rats and mice in relation to their effects on MAO. Selective inhibition of MAO B achieved following 18 h pretreatment with L-deprenyl and/or MDL 72145 did not per se lead to prominent pharmacological activity; no effects were seen in the mouse "Behavioural Despair" test, hypothermia induced by reserpine in mice was neither prevented nor reversed and there was no change in the cardiovascular responsiveness of the pithed rat to tyramine, noradrenaline or stimulation of the spinal sympathetic outflow. L-Deprenyl differed from MDL 72145 in that short term treatment with this drug caused positive effects in the "Behavioural Despair" test, reversal of reserpine hypothermia, indirect sympathomimetic stimulation of blood pressure and heart rate in the pithed rat and ipsilateral rotation in rats with unilateral nigro-striatal lesions. Qualitatively similar effects were seen with dexamphetamine. The marked difference between the pharmacological effects of MDL 72145 and L-deprenyl despite equivalent inhibition of MAO B suggests that many of the pharmacological actions of L-deprenyl result from its amphetamine-like sympathomimetic properties. MDL 72145 can, therefore, be considered a more reliable tool with which to explore the functional importance of MAO B inhibition in experimental animals and man.

Allylamine↗
PubMed1985

The depolarizing action of 5-hydroxytryptamine on rabbit vagal primary afferent and sympathetic neurones and its selective blockade by MDL 72222.

MDL 72222 (1 alpha H,3 alpha,5 alpha H-tropan-3-yl-3,5-dichlorobenzoate) is a novel compound with potent and selective blocking actions at certain excitatory 5-hydroxytryptamine (5-HT) receptors on mammalian peripheral neurones. In the present study, the sucrose-gap technique has been used to record depolarizing responses to 5-HT from the cells of the rabbit nodose and superior cervical ganglia and to investigate the potency and selectivity of MDL 72222 as an antagonist of these responses. On nodose ganglia, responses to 5-HT were inhibited surmountably by MDL 72222 at concentrations up to 100 nmol/l. The threshold for antagonism was 2-10 nmol/l and the apparent pA2 value (Schild 1947) was 7.7 +/- 0.2, n = 10. Blockade was selective since responses to GABA and noradrenaline were unaffected by MDL 72222, 100 nmol/l. With concentrations of MDL 72222 higher than 100 nmol/l, antagonism was concentration-related but not in a manner consistent with simple competitive antagonism and even a concentration of 1 mumol/l failed to abolish the response to 5-HT. The results from the superior cervical ganglion were essentially similar to those obtained from the nodose ganglion. The threshold concentration of MDL 72222 for inhibition of 5-HT was 1-10 nmol/l and blockade was selective in that depolarizing responses to dimethylphenyl-piperazinium (DMPP) was unaffected by a concentration of MDL 72222 of 1 mumol/l. The data provide direct evidence that MDL 72222 is a potent and selective antagonist of the receptors for 5-HT which mediate depolarizing responses in vagal primary afferent cell bodies and in sympathetic ganglion cells.

Animals↗
PubMed1985

Effects on migraine headache of MDL 72,222, an antagonist at neuronal 5-HT receptors. Double-blind, placebo-controlled study.

MDL 72,222 (1 alpha H, 5 alpha H-tropan-3 alpha-yl 3,5-dichlorobenzoate), a novel agent with antagonist activity at neuronal 5-HT receptors, was tested as an acute treatment for migraine pain under double-blind, placebo-controlled conditions. Forty-seven patients with common (n = 29) or classical (n = 8) migraine or mixed type with or without a psychogenic component (n = 10) received 20-40 mg MDL 72,222 (n = 24) or placebo (n = 23) intravenously during the headache phase of a migraine attack. MDL 72,222 was consistently superior to placebo in rapidly alleviating the migraine pain. The treatment was remarkably well tolerated. The results are consistent with the hypothesis that the pain of migraine is related to activation of neuronal 5-HT receptors and suggest that compounds such as MDL 72,222, which block neuronal 5-HT receptors, could be useful new therapeutic agents for the management of migraine.

Adult↗
PubMed1985

Inhibition of monoamine oxidase selectively in brain monoamine nerves using the bioprecursor (E)-beta-fluoromethylene-m-tyrosine (MDL 72394), a substrate for aromatic L-amino acid decarboxylase.

(E)-beta-Fluoromethylene-m-tyrosine (FMMT) is a dual-enzyme-activated inhibitor of monoamine oxidase (MAO). The compound is not an inhibitor per se but is decarboxylated by aromatic L-amino acid decarboxylase (AADC) to yield a potent enzyme-activated irreversible inhibitor of MAO, (E)-beta-fluoromethylene-m-tyramine, which shows some selectivity for inhibition of MAO type A. Decarboxylation of FMMT was demonstrated in vitro using hog kidney AADC and in vivo in rats by the ability of alpha-monofluoromethyldopa (MFMD), a potent inhibitor of AADC, to prevent MAO inhibition produced by FMMT. In isolated synaptosomes, FMMT was decarboxylated by AADC, and, furthermore, the compound was actively transported into these isolated nerve endings. An active transport into the CNS has also been demonstrated in vivo by performing competition experiments with leucine. To demonstrate that FMMT is preferentially decarboxylated within monoamine nerves of the CNS, the nigrostriatal 3,4-dihydroxyphenylethylamine (dopamine) pathway of rats was unilaterally lesioned with 6-hydroxydopamine or infused with MFMD. Under these conditions, MAO inhibition produced by orally administered FMMT in the striatum ipsilateral to the lesion or infusion was markedly attenuated. Combination of FMMT with an inhibitor of extracerebral AADC, such as carbidopa, protected peripheral organs against the MAO inhibitory effects and concomitantly enhanced MAO inhibition in the CNS. Such combinations had a greatly reduced propensity to augment the cardiovascular effects of intraduodenally administered tyramine, when compared with FMMT given alone or with clorgyline, a selective inhibitor of MAO type A. The results obtained with FMMT suggest the possibility of achieving selective inhibition of MAO within monoamine nerves of the CNS and, further, suggest that combination of FMMT with an inhibitor of extracerebral AADC will reduce the propensity of this inhibitor to produce adverse interactions with tyramine.

Animals↗
PubMed1984

The involvement of subtypes of the 5-HT1 receptor and of catecholaminergic systems in the behavioural response to 8-hydroxy-2-(di-n-propylamino)tetralin in the rat.

The centrally active 5-HT receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) has a high affinity for the 5-HT1A subtype of the 5-HT1 recognition site in cerebral membranes and, in the rat, induces most aspects of the '5-HT behavioural syndrome' including hyperlocomotion, head weaving, a flat body posture and reciprocal forepaw treading. The mechanism of action of 8-OH-DPAT in producing these effects has been investigated. Consistent with an involvement of catecholaminergic neurons, reserpine dose-dependently reduced hyperlocomotion and head weaving, and most components of the syndrome were reduced by prazosin, haloperidol and sulpiride. However, reserpine did not block forepaw treading or the flat body posture, allowing pharmacological analysis of these behaviours in the absence of intact monoaminergic systems. Under these circumstances blockade by the selective 5-HT2 receptor antagonist, ketanserin, and by haloperidol was not seen, and only the flat body posture was significantly reduced by prazosin, rendering a key role for 5-HT2 receptors, alpha 1-adrenoceptors and dopamine receptors unlikely. In contrast, both behaviours in the reserpinised rat were inhibited stereospecifically by pindolol and by spiperone, which interact with 5-HT1 and 5-HT1A recognition sites. The residual behavioural effects of 8-OH-DPAT in reserpinised rats may, therefore, reflect the consequences of stimulation of the putative 5-HT1A receptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1984

MDL 72222: a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors.

The properties of MDL 72222 (1 alpha H, 3 alpha, 5 alpha H-tropan-3-yl-3,5-dichlorobenzoate), a novel compound with potent and selective blocking actions at certain excitatory 5-hydroxytryptamine (5-HT) receptors on mammalian peripheral neurones, are described. On the rabbit isolated heart, MDL 72222 was a potent antagonist of responses mediated through the receptors for 5-HT present on the terminal sympathetic fibres. The threshold for antagonism was approximately 0.1 nM and the negative logarithm of the molar concentration of MDL 72222 which reduced the chronotropic response of the isolated rabbit heart to twice an ED50 of 5-HT to that of the ED50 was 9.27. MDL 72222 was also highly selective since responses to the nicotine receptor agonist, dimethylphenylpiperazinum iodine (DMPP), were inhibited only at concentrations more than 1000 times those necessary to inhibit 5-HT. In the anaesthetised rat, MDL 72222 produced marked blockade of the Bezold-Jarisch effect of 5-HT. Again, inhibition was selective since much higher doses of MDL 72222 failed to alter the response to electrical stimulation of the efferent vagus nerves. In contrast, MDL 72222 proved only a weak and essentially non-selective antagonist of responses mediated by the 5-HT M-receptor present on the cholinergic nerves of the guinea-pig ileum. MDL 72222 does not block smooth muscle contractile responses elicited by oxytocin or mediated through 5-HT D-receptors, muscarinic or nicotinic cholinoceptors or histamine H1-receptors except at relatively high concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1984

Neuronal 5-HT receptors in the periphery.

5-Hydroxytryptamine (5-HT) induces responses in neurones from all branches of the mammalian peripheral nervous system. Responses may be excitatory or inhibitory and are mediated through at least four distinct receptor sites. One receptor mediates excitation in motoneurones and preganglionic sympathetic neurones and can be designated a D (or possibly 5-HT2) receptor since "classical" antagonists such as methysergide, metergoline or cinanserin are potent and selective antagonists at this site. A second receptor mediating neuronal excitation can be positively identified on the basis of susceptibility to blockade by small concentrations of 1 alpha H,3 alpha,5 alpha H-tropan-3-yl-3,5-dichlorobenzoate (MDL 72222) and the weak or negligible affinity, relative to 5-HT, of certain agonists such as 5-methoxytryptamine. Such sites mediate depolarization of sympathetic and parasympathetic neurones and excitation of both the cell bodies and terminals of primary afferent fibres. A third receptor, mediating neuronal excitation, is the classical M-receptor of Gaddum and Picarelli, at this stage clearly identified only on postganglionic parasympathetic neurones of the guinea-pig myenteric plexus. These sites can be differentiated from other excitatory 5-HT receptors since MDL 72222 is neither potent nor selective as an antagonist and 5-methoxytryptamine approaches the potency of 5-HT as an agonist. (3 alpha-Homotropanyl)-1-methyl-5-fluoro-indole-3-carboxylic acid is a potent, surmountable antagonist of 5-HT at the M-receptor of the ileum, but is non-selective. Neuronal inhibitory responses have been observed using electrophysiological techniques or by monitoring the decrease in depolarization-evoked release of transmitter in enteric, parasympathetic and sympathetic neurones. Largely negative results, using selective agonists and antagonists, allow the receptor(s) mediating inhibition to be clearly differentiated from the three neuronal excitatory receptors for 5-HT. Comparison of relative potencies of agonists suggests similarities with the 5-HT1 recognition site of the central nervous system; no selective antagonist has yet emerged to permit their positive identification.

Animals↗