Martin Tulp

Flesinoxan lowers blood pressure and heart rate in cats via 5-HT1A receptors.

Flesinoxan, a new phenylpiperazine derivative has been shown to lower blood pressure in different species after both oral and i.v. administration. The present study shows that the hypotensive potency of flesinoxan in anaesthetised cats increased 35 times after administration via the vertebral arteries compared to i.v. administration. These results, which were confirmed by intracisternal administration, point strongly to a central site of action. Haemodynamic studies indicated that the blood pressure reduction in anaesthetised cats was mainly due to a reduction in the total peripheral resistance and only to some extent to a reduced cardiac output. Flesinoxan seems not to affect sympathetic function by a peripheral mechanism. Its cardiovascular profile can be explained by a centrally mediated reduction of sympathetic tone and increase in vagal tone. Receptor binding studies indicated that flesinoxan is a very potent and selective 5-HT1A ligand. The decreases in blood pressure and heart rate induced by centrally administered flesinoxan and 8-OH-DPAT, could be antagonized effectively by the putative 5-HT1A antagonist pindolol. This suggests a relationship between blood pressure reduction and central 5-HT1A receptors.

Unconventional natural sources for future drug discovery

‘There are more things between heaven and earth…’ Despite the progress of science during the past four centuries, Shakespeares words did not lose their actuality. Knowledge about the etiology of diseases is still limited, and for many life-threatening illnesses no effective treatments exist. Nature always has been a valuable source of drugs and, despite the unprecedented opportunities afforded by medicinal chemistry, continues to deliver lead compounds. Traditionally, research on natural sources was focused on terrestrial plants and microorganisms. More recently, however, organisms of marine origin are also being investigated. Here, the possibilities of unconventional and hardly explored sources are discussed.

Evaluation of the receptor selectivity of the H3 receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5‐HT3 receptor revealed

1 In the present study we evaluated the receptor selectivity of the potent histamine H3 receptor antagonist, iodophenpropit (IPP) in comparison with the prototype antagonist, thioperamide. 2 IPP proved to be a potent competitive H3 receptor antagonist as measured against (R)‐α‐methylhistamine‐induced inhibition of electrically‐evoked contractions of the guinea‐pig jejunum (pA2=9.12±0.06, Schild slope: 1.0±0.1, n=8). In the same assay, thioperamide was slightly less potent (pA2 = 8.9±0.2). 3 In radioligand binding studies, IPP showed a high affinity for the H3 receptor. Displacement of [125I]‐IPP binding to rat cortex membranes by unlabelled IPP resulted in a Ki value of 0.97 ± 0.06 nM (n = 3). In contrast, IPP showed only a weak affinity for the histamine H1‐ and H2 receptor. Displacement of [3H]‐mepyramine and [125I]‐iodoaminopotentidine binding to respectively guinea‐pig H1‐ and human H2 receptors by IPP resulted in Ki values of 1.71±0.32 μm (n=3) and 2.28±0.81 μm (n=3). For thioperamide the affinities for the H1‐, H2‐ and H3 receptor were respectively >10 μm, >10 μm and 4.3±1.6 nM (n=7). 4 Testing IPP and thioperamide in 39 different receptor binding assays revealed that IPP showed relatively high affinity for the 5‐hydroxytryptamine 5‐HT3 receptor (Ki=11± nM, n=3), the α2‐adrenoceptor (Ki=120±5 nM, n=3) and the sigma receptor (Ki=170±70 nM, n=3). Thioperamide showed relatively high affinity for the 5‐HT3 receptor (Ki=120±30 nM, n=3) and the sigma receptor (Ki=180±90 nM, n=3). 5 Due to the low density of histamine H3 receptors in the brain, the interaction of IPP with the 5‐HT3‐, the α2‐ and the sima receptor might interfere with [125I]‐IPP binding to rat cortex membranes. Yet, in this preparation [125I]‐IPP binding was not influenced by ondansetron, yohimbine or haloperidol. 6 The interaction with the 5‐HT3 receptor was not restricted to IPP or thioperamide, but was also found with other H3 receptor antagonists. The potent H3 receptor agonist imetit, a compound belonging to the same chemical class of IPP, also interacted with the 5‐HT3 receptor (Ki=240±40 nM). In contrast, histamine or the H3 receptor agonist, (R)‐α‐methylhistamine showed no affinity for the 5‐HT3 receptor. 7 In the guinea‐pig isolated ileum, imetit evoked concentration‐dependent contractions, resulting in a pD2 value of 4.72±0.03 (n = 9). The contractions were antagonized by ondansetron, yielding a pA2 value of 7.1±0.1 (n=9). Similarly ondansetron antagonized the contractions evoked by the 5‐HT3 receptor agonist, 2‐methyl‐5‐HT with a pA2 value of 7.3±0.1 (n=4). IPP and thioperamide did not mimic 2‐methyl‐5‐HT but non‐competitively inhibited the 2‐methyl‐5‐HT‐induced contractions of this preparation. 8 In an in vivo model for 5‐HT3 activity, the Von Bezold Jarisch reflex, thioperamide showed antagonism in low dosages, which correlated well with the affinity for the 5‐HT3 receptor site. Yet, at higher dosages no further 5‐HT3 receptor antagonism was observed. For IPP no 5‐HT3 receptor activity could be observed in vivo. 9 In the present study we showed that many H3 receptor compounds, that are regarded as highly selective (including the prototype drug, thioperamide), also interact with the 5‐HT3 receptor, albeit at higher drug concentrations.

Serotonergic Modulation of Agonistic Behaviour

Over the last fifteen years several hypotheses have emerged concerning the neurochemical control of aggressive behaviour. A variety of single neurotransmitters were suggested to control. aggression e.g. the “aggressive monoamines” (Eichelman and Thoa 973), acetylcholine (Smith et a1. 1970) and serotonin (Valzelli and Garattini 1968). Later, the theories of single neurotransmitter control were extended to multi-transmitter modulation of aggressive behaviour (Avis 1974; Daruna 1978; Pradhan 1915; Reis 1974).

New 1-aryl-4-(biarylmethylene)piperazines as potential atypical antipsychotics sharing dopamine D2-Receptor and serotonin 5-HT1A-Receptor affinities

This paper describes the syntheses of several 1-aryl-4-(biarylmethylene)piperazines and the results of the determination of their affinity for D(2) and 5-HT(1A) receptors. A selection of these compounds was evaluated in vivo, resulting in the identification of a drug candidate which is being clinically evaluated as a potential atypical antipsychotic with reduced extrapyrimidal side effects.

SLV310, a novel, potential antipsychotic, combining potent dopamine D2 receptor antagonism with serotonin reuptake inhibition

In this paper, SLV310 is presented as a novel, potential antipsychotic displaying the interesting combination of potent dopamine D(2) receptor antagonism and serotonin reuptake receptor inhibition in one molecule. As such, SLV310 could be useful in treating a broad range of symptoms in schizophrenia. This paper describes the structure-activity relationship in a series of compounds leading to SLV310 (6b, 2-[4-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl]-phthalimide) together with pharmacological data showing the unique profile of this compound.

Synthesis and structure–Activity data of some new epibatidine analogues

The high-pressure Diels-Alder reaction of N-carbomethyoxypyrroles and phenyl vinyl sulfone affords versatile intermediates for the palladium-catalyzed preparation of new epibatidine analogues. Structure-activity relationships of new epibatidine analogues are presented. High affinities of Ki = 0.81 and 2.6 nM for the [3H]-cytisine rat brain nicotinic acetylcholine binding sites were found for the 5-pyrimidinyl and the 5-(2-amino)-pyrimidinyl epibatidine analogues, respectively.

Adrenoceptors and dopamine receptors are not involved in the discriminative stimulus effect of the 5-HT1A receptor agonist flesinoxan.

Using a two-lever operant drug discrimination procedure, rats were trained to discriminate the 5-HT1A receptor agonist, flesinoxan (0.5 mg/kg i.p.), from saline. Hereafter, several non-serotonergic drugs were tested in generalization and antagonism tests. The flesinoxan stimulus did not generalize to the stimuli of either the alpha 1-adrenoceptor antagonist, prazosin, the alpha 2-adrenoceptor agonist, clonidine, the dopamine receptor agonist, apomorphine, the dopamine receptor antagonists, haloperidol and pimozide, the benzodiazepine receptor agonist, chlordiazepoxide, nor to the peripherally acting vasodilator, hydralazine. In antagonism studies, prazosin, haloperidol, pimozide and the alpha 2-adrenoceptor antagonist, idazoxan, failed to block the flesinoxan stimulus. In substitution tests, however, flesinoxan partially generalized to idazoxan and completely to the alpha 2-adrenoceptor antagonist, yohimbine. The affinities of yohimbine and idazoxan for the 5-HT1A receptor may explain the latter result. The present findings suggest that the central mechanism through which flesinoxan exerts its discriminative stimulus effects does not involve alpha 1- and alpha 2-adrenoceptors, dopamine and benzodiazepine receptors. Finally, the results with the blood pressure lowering agents, hydralazine, clonidine and prazosin do not support the suggestion that the centrally mediated blood pressure lowering effects of flesinoxan contribute to its internal stimulus effect.

C5-Substituted Derivatives of 5-OMe-BPAT: Synthesis and Interactions with Dopamine D2 and Serotonin 5-HT1A Receptors

Eight new C5-substituted derivatives of the potential atypical antipsychotic agent 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (5-OMe-BPAT, 1) have been prepared by chemical conversion of the 5-trifluoromethylsulfonyloxy (triflate) analogue 4 via various Stille-type cross-couplings, a Heck reaction, and an amidation in moderate to good yields. The 5-acetyl, 5-cyano, 5-methyl, 5-(2-furyl), 5-phenyl, methyl 5-carboxylate, and the 5-carboxamido analogues 5-11 thus obtained, the previously disclosed 5-methoxy, 5-hydroxy, and 5-unsubstituted analogues 1-3, and the 5-triflate analogue 4 were evaluated for their ability to compete for [3H]-spiperone binding to rat striatal membranes containing dopamine D2 receptors, and their ability to compete for [3H]-8-OH-DPAT binding to rat frontal cortex membranes containing serotonin 5-HT1A receptors in vitro. Compounds 1-11 displayed weak to high affinities for dopamine D2 receptors, with Ki-values ranging from 550 nM for the 5-carboxamido analogue to 4.9 nM for the 5-hydroxy analogue. The relative affinities of the 5-methoxy, 5-hydroxy, and 5-unsubstituted analogues suggested that these compounds may bind to the same site and in a similar way as the 5-oxygenated DPATs, with the 5-methoxy substituent of 1 functioning as a hydrogen bond acceptor. The serotonin 5-HT1A receptor tolerated more structural diversity at the C5-position of 1, as revealed by the higher Ki-values of 1-11, which ranged from 60 nM for the 5-carboxamido analogue to 1.0 nM for the 5-unsubstituted analogue. Partial least-squares (PLS) analysis of a set of 24 molecular descriptors, generated for each analogue, revealed no significant correlation between the dopamine D2 receptor affinities of 1-11 and their molecular properties, supporting the view that they may have different binding modes at this receptor subtype. A PLS model with moderate predictability (Q2 = 0.49) could be derived for the serotonin 5-HT1A receptor affinities of 1-11. According to the model, a relatively lipophilic, nonpolar C5-substituent should be optimal for a high affinity at this receptor subtype.

Idaverine, an M2- vs. M3-selective muscarinic antagonist, does not prevent motion sickness in cats

In this study, the affinity profile of idaverine for the M1- (neuronal tissue), M2- (heart) and M3- (glandular tissue/nonvascular smooth muscle) muscarinic receptors was examined by means of radioligand binding and in vitro organ bath experiments in order to use the compound for the investigation of the muscarinic receptor subtype involved in motion sickness. In the profile study a comparison was made with the muscarinic antagonists atropine, pirenzepine (M1-selective) AF-DX 116 (M2-selective) and 4-DAMP (high affinity for M1- and M3-binding sites). The affinity of idaverine appeared to be equally high for the M1- and M2-binding sites. However, the affinity for the M1-binding sites should be interpreted cautiously since the Hill slope deviated from unity. Idaverine showed a 20-fold selectivity for the M2-binding sites over the M3-binding sites, whereas it showed a small selectivity (less than 5-fold) for the M2-receptors compared to the ileal and tracheal smooth muscle receptors. Thus idaverine appears to be M2 over M3 selective. However, in contrast to AF-DX 116, it is not clear whether idaverine is also M2 over M1 selective. In experiments with cats, idaverine failed to prevent motion sickness at doses from 0.03 to 3 mg/kg. These results are interpreted to implicate M3-receptors in the motion sickness suppressant effect of antimuscarinic drugs.