Effects of phosphodiesterase V inhibition on nitric oxide-mediated relaxation responses in guinea pig trachea

In the present study, we aimed to evaluate the effects of PDE V inhibition on NO-mediated relaxation responses in isolated guinea pig trachea. Under the NANC conditions, tracheal preparations were contracted with histamine (100 microm/l). When contraction had reached a plateau, relaxation responses to electrical field stimulation (EFS, 60 V, 0.5 ms, 5-10 Hz) were determined before and after incubation of the tracheal ring with L-NAME (1 mmol/l), a NO synthase inhibitor. L-NAME significantly inhibited the relaxation responses and this inhibitory effect was reversed by L-arginine (1 mmol/l), a precursor of NO, but was not affected by D-arginine. In addition, cumulative application of the NO donors, 3-morpholino-sydnonimine (SIN-1) and sodium nitroprusside (SNP), caused concentration-dependent relaxation of tissues precontracted with histamine. The selective PDE type V inhibitor zaprinast at EC50 concentration (30 micromol/l) significantly potentiated EFS-induced NANC relaxations and relaxant responses to SIN-1 and SNP. In conclusion, these data support the hypothesis that NO is a mediator of NANC relaxations of guinea pig tracheal rings and PDE V inhibition potentiates NO-mediated relaxation.     

A new class of nitric oxide-releasing derivatives of cetirizine; pharmacological profile in vascular and airway smooth muscle preparations

BACKGROUND AND PURPOSE: The pharmacological properties of compounds NCX 1512 and NCX 1514, synthesized by linking the histamine H1-receptor antagonist cetirizine to NO-releasing spacer groups, are reported. The aim was to establish if the compounds retained the antihistamine action of the parent compound, to assess their efficacy as NO donors and to test if they had broader antiallergic activity than cetirizine in the lung. EXPERIMENTAL APPROACH: Antihistamine activity of NCX 1512 and NCX 1514 was investigated in vitro in the guinea pig ileum, in tracheal rings (GPTR) and lung parenchymal strips (GPLP) of the guinea-pig. The NO-releasing capacity was investigated in vascular preparations; the isolated rabbit and guinea-pig aorta and guinea-pig pulmonary artery. Kinetics of NO release were assessed in a rat whole blood assay. KEY RESULTS: Both NCX 1512 and NCX 1514 retained activity as H1-receptor antagonists in the guinea pig ileum and airway preparations. The NO-releasing NCX compounds relaxed the rabbit aorta, an action prevented by the guanylyl cyclase inhibitor ODQ (10 microM). NCX 1512 and NCX 1514 did not relax the antigen (ovalbumin) pre-contracted GPTR, whereas the NO donors NCX 2057 and DEA-NONOate relaxed guinea-pig pre-contracted vascular and tracheal preparations. Cetirizine (1-100 microM) and NCX 1512 (1-100 microM) reduced the cumulative (0.01-100 microg ml(-1)) ovalbumin-induced constriction in GPTR, but had no significant effect in GPLP. CONCLUSIONS AND IMPLICATIONS :NCX 1512 and NCX 1514 act as antihistamines and NO donors. However, there was no improved effect compared to cetirizine on antigen-induced constriction of the central and peripheral lung.     

Polyalthic Acid Isolated from Croton reflexifolius has Relaxing Effect in Guinea Pig Tracheal Smooth Muscle

The relaxing activity of Croton reflexifolius H.B.K (Euphorbiaceae) leaves was assessed in isolated guinea pig tracheal rings. The dichloromethane extract of C. reflexifolius was the most active relaxant (EC₅₀ = 118.98 ± 5.927 μ g/mL), and within this extract polyalthic acid was identified as the main active relaxing agent. Polyalthic acid showed a relaxing effect on tracheal rings precontracted with carbachol (EC₅₀ = 183.71 ± 3.28 μM), histamine (6.24 ± 0.28 μM), and KCl (195.79 ± 10.36 μM). The pretreatment with polyalthic acid did not affect the concentration response curve to histamine, and it reduced the Emax of carbachol without affecting its EC₅₀, thus suggesting that polyalthic acid produces a mild antimuscarinic activity. In addition, neither glibenclamide, l-NAME nor propranolol modified the effect of polyalthic acid, although the latter enabled isoproterenol activity. In conclusion, this study represents the first in which the relaxing effect of C. reflexifolius on tracheal rings of guinea pig was clearly demonstrated. Polyalthic acid, which was the main active agent in this relaxing action, produced a mild antimuscarinic activity in a noncompetitive manner. Its relaxing effect was independent of the contractile agent employed and was not related with β -adrenergic receptors, K channels, or nitric oxide. Further experiments are needed to clarify the mechanism of action of polyalthic acid.     

Contractile activity of the N-acylated C-terminal part of substance P7–11 in guinea pig trachea

Summary Substance P, neurokinin A, neurokinin B, and N-acylated pentapeptide X-Phe-Phe-Gly-Leu-Met-NHin2 analogs of substance P_7–11 were tested for their spasmogenic activities in intact or in epithelium-denuded tracheal strips from guinea pig. Epithelium removal enhanced the efficacies and potencies relative to substance P of all the peptides tested in guinea pig trachea. In epithelium-containing preparations, the presence of a cyclic substituent (o-hydroxyphenyl-acetyl, p-hydroxyphenyl-acetyl, pyroglutamyl) in Phe⁷ greatly enhanced the potency and efficacy compared to substance P. These substitutions were twice as active as neurokinin A itself. The presence of an aliphatic chain (non-protected and t-butyloxycarbonyl-protected aminopropyl and aminocaproyl) in Phe⁷ also improved the potency and the efficacy of the synthetic peptides. The aliphatic substituents could favour an increase in local concentration of the peptides in the vicinity of the receptor(s) allowing a more effective ligand-receptor interaction. Thus, lipophilicity could be determinant in the potency of the peptides in intact guinea pig trachea. In epithelium-denuded tracheal strips from guinea pig, all the synthetic peptides were more effective than substance P but less active than neurokinin A which probably reflects the presence of the NK₂ receptor subtype, which may be predominant in this type of epithelium-denuded preparation. Our results suggest that hydrophobicity plays a strong role in the interaction of the peptides, namely substance P and its analogues with the membrane and possibly the receptors themselves.Send offprint requests to E. Tschirhart at the above address     

沙丁胺醇的抗过敏作用及酮替芬对其平喘效应的增强作用

目的　观察沙丁胺醇的抗过敏作用及酮替芬对沙丁胺醇平喘效应的增强作用。方法　用豚鼠离体气管实验法,组胺、乙酰胆碱引喘法,致敏豚鼠离体气管Ｓｃｈｕｌｔｚ Ｄａｌｅ 反应及支气管肺泡灌洗液中嗜酸粒细胞数测定法。结果　酮替芬可增强沙丁胺醇的松弛气道平滑肌作用和预防沙丁胺醇引起的β受体快速耐受性的产生;酮替芬还可增强沙丁胺醇抑制组胺、乙酰胆碱引起的豚鼠哮喘;沙丁胺醇和酮替芬对致敏豚鼠离体气管Ｓｃｈｕｌｔｚ Ｄａｌｅ 反应具有抑制作用,并能使过敏性哮喘迟发反应时豚鼠支气管肺泡灌洗液中嗜酸粒细胞数显著减少。结论　沙丁胺醇具有抗过敏作用,酮替芬可预防沙丁胺醇耐受性的产生和增强沙丁胺醇的平喘效应     

Iodoaminopotentidine and related compounds: a new class of ligands with high affinity and selectivity for the histamine H2 receptor.

The synthesis and biological evaluation of a new class of histamine H2 antagonists with N-cyano-N'-[omega-[3-(1-piperidinylmethyl)phenoxy] alkyl]guanidine partial structure are described as part of an extensive research program to find model compounds for the development of new radioligands with high H2 affinity and specific activity. High receptor affinity is achieved by an additional (substituted) aromatic ring, which is connected with the third guanidine N by a carbon chain spacer and an amine, carboxamide, ester, or sulfonamide link ("polar group"). In functional studies for H2 antagonistic activity and other pharmacological actions [e.g. H1 antihistaminic, antimuscarinic, antiadrenergic (alpha 1, beta 1), 5-HT2 blocking activity] in the isolated guinea pig atrium and ileum and rat aorta and tail artery, the compounds proved to be highly potent and selective histamine H2 receptor antagonists. The H2 antagonistic activity is mainly depending on the length of both the N'-alkyl chain (chain A) and the N"-spacer (chain B). Compounds with a C3 chain A and a C2 chain B are most potent in the preferred group of substances, i.e., the carboxamide series. A wide variety of substituents at the aromatic ring is tolerated, among them iodine, amino, and azido groups. These compounds are up to 32 times more potent than cimetidine in the isolated guinea pig right atrium. The replacement of the carboxamide by an ester group (44c) is well tolerated, while replacement of the cyanoguanidine by an urea group results in nearly 100-fold decrease in activity (46c,e). The iodinated benzamides are among the most potent H2 antagonists known so far. The [125I]-labeled form of 31f ([125I]iodoaminopotentidine, [125I]-N-[2-(4-amino-3-iodobenzamido) ethyl]-N'-cyano-N"-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]guanidine) and its photolabile analogue 31h ([125I]iodoazidopotentidine, [125I]-N-[2-(4-azido-3- iodobenzamido)ethyl]-N'-cyano-N"-[3-[3-(1-piperidinyl-methyl)pheno xy] propyl]guanidine) proved to be useful probes for reversible and irreversible labeling of the histamine H2 receptor. Radioligand binding studies in guinea pig cerebral membranes revealed considerably higher H2 receptor affinity for 31f (pKi = 9.15), 31h (pKi = 8.58), and some analogues than functional experiments (guinea pig atrium), presumably reflecting an easier access to the H2 receptors in membranes.     

Evaluation of Antiasthmatic Activity of Curculigo orchioides Gaertn. Rhizomes

The ethanol extract of Curculigo orchioides was evaluated for antiasthmatic activity by using various in vitro and in vivo animal models. In vitro models like isolated goat tracheal chain preparation and isolated guinea pig ileum preparation were studied to know basic mechanism by which extract shows relaxant activity. The study showed that extract is effective against histamine-induced contraction. In isolated goat tracheal chain preparation and isolated guinea pig ileum preparation extract exhibits maximum relaxant effect (p< 0.01) against histamine at concentrations 100μg/ml and 25μg/ml respectively. Animal studies involved use of histamine induced bronchoconstriction in guinea pigs, egg albumin induced passive paw anaphylaxis in rats and haloperidol-induced catalepsy in mice. These studies showed significant (p< 0.01) protection at lower doses while further increase in the dose level showed reduced activity. Biochemical estimations in milk-induced total leukocytes count and milk-induced differential leukocyte count were also studied. In this study there was maximum increase in leucocytes and lymphocytes (99%) and maximum decrease in eosinophils up to 0% at dose 375mg/kg p.o. body weight was observed. The results of these studies indicated usefulness of ethanol extract of Curculigo orchioides in asthma.     

Benzo[1,2-c:5,4-c']dipyrazoles: non-xanthine adenosine antagonists

3,5-Dimethylbenzo[1,2-c:5,4-c']dipyrazoles, optionally substituted in the 1-, 7-, and 8-positions, were synthesized from resorcinols. These compounds display affinity for adenosine A1 (rat brain) and A2 (human platelet) receptors. In addition, these compounds reverse contractions of guinea pig tracheal cylindrical segments induced by potassium chloride, histamine, acetylcholine, and 5-hydroxytryptamine, as well as reverse bronchospasm induced by aerosolized histamine in the conscious guinea pig.     

金荞麦对家鸽气管纤毛运动和豚鼠离体气管平滑肌舒张的影响

目的研究金荞麦对家鸽纤毛运动和豚鼠离体气管平滑肌舒张的影响。方法气管纤毛运动试验观察不同剂量金荞麦(6,3,1.5 g生药/kg)对家鸽纤毛运动的影响;制备新鲜的豚鼠离体气管片,在K-H缓冲液中观察不同剂量的金荞麦(累积浓度为15,30,60,120 g生药/L)对气管片收缩的影响;制备新鲜的豚鼠离体气管螺旋条,在K-H缓冲液加入组胺,使豚鼠气管螺旋条收缩达高峰后观察不同剂量的金荞麦(15,30,60,120g生药/L)对组胺致气管片收缩的影响。结果金荞麦三个剂量组均能加快家鸽气管内纤毛运动速度(P<0.01或P<0.05);金荞麦60～120 g生药/L溶液能明显松弛正常豚鼠离体气管平滑肌(P<0.01或P<0.05);金荞麦15～120 g生药/L溶液对组胺致豚鼠离体气管平滑肌收缩有明显解痉作用(P<0.01)。结论金荞麦可明显加快家鸽气管纤毛运动;金荞麦可明显松弛豚鼠离体气管平滑肌,并具有一定的浓度依赖性;并对组织胺致豚鼠离体气管平滑肌收缩有明显解痉作用,并呈现一定的浓度依赖性。     

Actions of 5'-methylthioadenosine in isolated guinea pig tracheal rings

The effects of 5'-methylthioadenosine (MTA) on smooth muscle were investigated using isolated guinea pig tracheal rings. MTA, at high concentrations caused the relaxation of isolated guinea pig tracheal rings in a concentration-dependent manner. These actions were pronounced in the tracheal rings contracted by histamine or leukotriene D4. The tracheal contractions induced by varying doses of histamine or leukotriene D4 were also suppressed by pretreatment of relatively low doses of MTA in a dose-dependent manner. Pretreatment of the tracheal rings with propranolol, tetrodotoxin, indomethacin and dipyridamole did not block the actions of MTA. In contrast, theophylline blocked the effects of MTA. These results suggested that MTA action on tracheal smooth muscle cells may be mediated by direct action on adenosine receptors.     

普罗托品松弛气管平滑肌的作用机制研究

目的　为评价普罗托品 (Pro)作为平喘药侯选者的可能性提供资料。方法　①观察不同浓度Pro对组胺、乙酰胆碱收缩的豚鼠离体气管螺旋条的舒张作用及其量效反应。②放射免疫法测定Pro对家兔气管平滑肌中环腺苷酸 (cAMP)、环鸟苷酸(cGMP)水平的影响。③高效液相色谱法检测Pro对豚鼠气管平滑肌磷酸二酯酶 (PDE)活性的影响。结果　①Pro能明显抑制组胺和乙酰胆碱引起的豚鼠离体气管条收缩 ,使其量效曲线右移 ,最大反应压低 ,pD2 ′分别为 3.11和 3.4 5。②Pro能增加家兔气管平滑肌中cAMP水平 ,而cGMP水平的变化无统计学意义。③Pro能抑制水解cAMP的PDE活性 ,但水解cGMP的PDE活性无明显降低。结论　Pro可抑制豚鼠气管平滑肌的收缩 ,其作用机制之一可能为其抑制气管平滑肌PDE活性 ,主要通过提高细胞中cAMP水平 ,进而松弛气管平滑肌     

N(alpha)-imidazolylalkyl and pyridylalkyl derivatives of histaprodifen: synthesis and in vitro evaluation of highly potent histamine H(1)-receptor agonists

A novel series of N(alpha)()-imidazolylalkyl and pyridylalkyl derivatives of histaprodifen (6, 2-[2-(3,3-diphenylpropyl)imidazol-4-yl]ethanamine) was synthesized and evaluated as histamine H(1)-receptor agonists. The title compounds displayed partial agonism at contractile H(1)-receptors of guinea pig ileum and were at least equipotent with histamine. Agonist effects of the new derivatives were susceptible to blockade by the H(1)-receptor antagonist mepyramine (2-100 nM). In the imidazole series, suprahistaprodifen (51, [2-[2-(3,3-diphenylpropyl)-1H-imidazol-4-yl]ethyl]-[2-(1H-imidazol-4-yl)ethyl]amine, N(alpha)-2-[(1H-imidazol-4-yl)ethyl]histaprodifen) showed the highest H(1)-receptor agonist potency ever reported in the literature (pEC(50) 8.26, efficacy E(max) 96%). Elongation of the alkyl spacer from ethyl to butyl decreased activity from 3630% (ethyl, 51) to 163% (butyl, 53) of histamine potency. The exchange of the terminal imidazole nucleus for a pyridine ring resulted in compounds with comparably high potency. A decrease in agonist potency and efficacy was observed when the attachment of the alkyl spacer was consecutively changed from the ortho to the meta and the para position, respectively, of the pyridine ring. The pyridine series that contained a butyl chain possessed the highest potency and affinity. N(alpha)-[4-(2-pyridyl)butyl]histaprodifen (56) emerged as a strong partial agonist, being almost equipotent with 51 (pEC(50) 8.16, E(max) 89%). Compounds 51 and 56 also showed potent partial agonism at contractile H(1) receptors in guinea pig aorta and potently activated H(1)-receptor-mediated endothelium-dependent relaxation in the rat aorta. Compounds 51-65 displayed low to moderate affinity at H(2), H(3), and M(3) receptors in functional models of guinea pig. Collectively, N(alpha)-imidazolylalkyl- and N(alpha)-pyridylalkyl-substituted histaprodifens represent a novel class of potent H(1)-receptor agonists. These compounds may be useful to define the (patho)physiological role of the H(1)-receptor and refine molecular models of H(1)-receptor activation.     

N-(heterocyclic alkyl)pyrido[2,1-b]quinazoline-8-carboxamides as orally active antiallergy agents

A series of N-(heterocyclic alkyl)pyrido[2,1-b]quinazoline-8-carboxamides were evaluated for their ability to antagonize slow-reacting substance of anaphylaxis (SRS-A) induced contractions of guinea pig ilea and to inhibit thromboxane synthase in vitro. The results indicated that those pyrido[2,1-b]quinazoline-8-carboxamides bearing a branched-chain alkyl moiety in the 2-position and a four to six atom linear chain between a 3- or 4-substituted pyridine or a 1-substituted imidazole ring and the carboxamide nitrogen atom showed the best combination of potencies in the two assays. Several of these compounds were found to be orally active inhibitors of LTE4-induced bronchoconstriction in the guinea pig and LTE4-induced skin wheal formation in the rat. One of the most potent analogues, 2-(1-methyl-ethyl)-N-(1H-imidazol-1-ylbutyl)-11-oxo-11H-pyrido [2,1-b]quinazoline-8-carboxamide (36), was selected for extensive pharmacological investigation. It was found that this compound was not a specific inhibitor of LTE4-induced symptomatology, but exhibited more general activity by inhibiting bronchospasm in guinea pigs induced by LTC4, LTD4, PAF, and histamine and skin wheal formation in rats and guinea pigs induced by LTC4, LTD4, and PAF. In addition, 36 was orally active in the passive cutaneous anaphylaxis assay, suggesting that it also exhibits mediator release inhibitory activity. On the basis of the overall pharmacological profile of 36 and its closely related analogues, it was concluded that these compounds may be useful for the treatment of asthma.     

Zwitterionic analogues of cimetidine as H2 receptor antagonists

A series of analogues of the H2 receptor histamine antagonist cimetidine have been synthesized in which the dipolar cyanoguanidine group has been replaced by a number of zwitterionic moieties. Although none of the compounds is more effective than cimetidine in blocking histamine-stimulated tachycardia on the isolated guinea pig atrium, the activities of most of the compounds possessing rigid dipoles can be accounted for on the basis of dipole orientation relative to the common side chain and by considering the active species in each case to be the zwitterion. These findings are in general agreement with those found for analogues having conjugated groups as dipoles.     

Effect of coenzyme Q10, a quinone derivative, on guinea pig lung and tracheal tissue

In the present investigation, the effect of coenzyme Q10 (E-0216) on histamine or SRS-A (slow-reacting substance of anaphylaxis) release from passively sensitized guinea pig lung tissue and on the actions of various bronchoactive-agents in isolated perfused guinea pig tracheal strips was studied. The amount of histamine and SRS-A released from passively sensitized guinea pig lung tissue by the challenge of antigen showed a marked decrease by preincubating with coenzyme Q10. The percentage inhibition of histamine and SRS-A was biggest at the concentration of 10 micrograms/ml of coenzyme Q10. Prostaglandin F2 alpha-, acetylcholine-, serotonin-, and bradykinin-induced contractile responses in guinea pig tracheal strips did not show any significant increase by continuous infusion of coenzyme Q10 (0.05-5.0 micrograms/ml). On the other hand, histamine-induced contractile responses showed a significant increase by continuous infusion of 0.5 microgram/ml of coenzyme Q10. Isoprenaline (isoproterenol)- and salbutamol-induced relaxation responses in guinea pig tracheal strips did not show any significant decrease by continuous infusion of coenzyme Q10 (0.05-5.0 micrograms/ml). On the other hand, prostaglandin E2-induced relaxation responses showed a significant decrease by continuous infusion 0.05-5.0 micrograms/ml of coenzyme Q10.     

佛司可林类化合物对离体豚鼠气管条舒张作用的研究

目的研究佛司可林、异佛司可林、佛司可林G、J、A、I对磷酸组胺(His)、氯化乙酰胆碱(ACh)引起的离体豚鼠气管条收缩作用的影响。方法取豚鼠气管制成螺旋状气管条,用磷酸组胺、氯化乙酰胆碱诱发气管条收缩,按累积剂量法加入系列浓度的佛司可林、异佛司可林、佛司可林G、J、A、I,观察其对气管条收缩反应的舒张作用,记录各累积浓度下的量效曲线,计算解痉百分率。结果异佛司可林、佛司可林均能明显舒张由His、ACh引起的离体豚鼠气管条的收缩(P<0.01)。佛司可林G、J、A、I均能舒张由His引起的离体豚鼠气管条的收缩(P<0.01)。且随着剂量的增加,舒张作用也有所增强。结论佛司可林、异佛司可林、佛司可林G、J、A、I对His或ACh引起的离体豚鼠气管条的收缩均具有舒张作用。     

Histamine-like Activity of Albizia anthelmintica

The aqueous fraction of methanol extract of Albizia anthelmintica stimulated guinea pig ileum, guinea pig tracheal chain and relaxed the spontaneously contracting rat uterus. These effects were blocked by H 1 and H 2 antagonists chlorpheniarmine and ranitidine respectively which indicate histamine-like activity. The presence of histamine was confirmed by TLC analysis.     

Involvement of B2 receptors in the bradykinin-induced relaxation of guinea-pig isolated trachea.

1. The aim of this study was to determine the receptor type and involvement of arachidonic acid metabolites in bradykinin-induced relaxation of the guinea-pig isolated trachea. 2. In the resting tracheal preparation, bradykinin (0.1 nM-30 microM induced a concentration-related contractile response (pD2 = 8.8 +/- 0.3). The maximal tension (1056 +/- 321 mg) was observed at 0.3 microM bradykinin. In contrast, when tracheal preparations were pre-contracted with histamine (30 microM leading to a half-maximum response), a concentration-related relaxation was observed with bradykinin. At the highest concentration of bradykinin used (3 microM), a reversal of 63 +/- 13% of the contractile response to histamine was observed. Both effects of bradykinin were inhibited by the cyclo-oxygenase inhibitor, indomethacin (1 microM). In concentration-response curves, melittin (10 nM-1 microM), a direct activator of phospholipase A2, mimicked both effects of bradykinin. The highest concentration of melittin used (1 microM), induced a tension of 813 +/- 120 mg and led to the reversal of 41 +/- 8% of the contractile response to histamine. The contractile effect of melittin was inhibited in the presence of both indomethacin (1 microM) and AA861 (1 microM), a 5-lipoxygenase inhibitor. 3. [Des Arg9]-bradykinin (1 nM-3 microM), a B1-receptor agonist, was unable to relax precontracted guinea-pig tracheal preparations. The relaxation induced by bradykinin was antagonized by the B2 receptor antagonists, Hoe 140 (D-Arg0[Hyp3,Thi5,D-Tic7,Oic8]bradykinin) and NPC 17761 (D-Arg0[Hyp3,D-HypE(trans-thiophenyl)7,Oic8]bradykinin ).(ABSTRACT TRUNCATED AT 250 WORDS)     

β-丁香烯代谢产物和结构改造的研究

从β-丁香烯代谢产物中分离得到一种有药理活性的化合物,经光谱分析及化学反应证明其结构为β-丁香酮(8)。根据代谢产物的化学结构以及构-效关系理论,对β-丁香烯进行了结构改造研究,结果得到一种活性较强的半合成产物,为无定形长丝状物,其结构被鉴定为β-丁香烯醇(3)。药理实验表明化合物(8)及(3)对豚鼠离体气管平滑肌均有较强的松弛作用,化合物(3)还能明显抑制组织胺和乙酰胆碱诱发的豚鼠哮喘,其作用持久而毒性低,可望成为一种新型的平喘药物。     

The histamine H2 receptor agonist impromidine: synthesis and structure-activity considerations

Impromidine (1) is a potent and selective histamine H2 receptor agonist and its structure comprises a strongly basic guanidine group containing two different imidazole-containing side chains. In this paper we report the synthesis of analogues in which both of the side chains and the guanidine group are modified and tested as agonists or antagonists at histamine H2 receptors on guinea pig atrium. A protonated amidine group linked by a chain of three carbon atoms to a tautomeric imidazole ring appears to be an essential feature for agonist activity and it is suggested that the second imidazole-containing side chain in impromidine mainly contributes toward affinity for histamine H2 receptors.