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The effect of hexahydrocoenzyme Q4 and of α-tocopherol on the haemopoietic tissues of dystrophic rabbits on a vitamin E-deficient diet has been studied. Animals receiving this diet supplemented with α-tocopherol were still significantly subnormal compared with the pellet controls. The diet had a significantly depressive effect on bone marrow cell maturation and on myeloid precursor cell supply as well as on the growth rate. Both hexahydrocoenzyme Q4 and α-tocopherol elicited a limited biological response in the bone marrow at the dose level administered. Neither therapy produced a haematological response corresponding to the cellular levels found in the pellet control group. Animals on the vitamin E-deficient diet disclosed typical muscular lesions. Both hexahydrocoenzyme Q4 and α-tocopherol had a beneficial effect on these muscular lesions. It is considered that the biological activity of α-tocopherol is directly that of an antioxidant protecting the biosynthesis of coenzyme Q10 and that of hexahydrocoenzyme Q4 is essentially substitution for coenzyme Q10.

The actions of neurotensin and (Gln4)-neurotensin have been investigated on a number of isolated tissues. They were ineffective in contracting the guinea pig vas deferens, the rabbit aortic strip or the frog rectus abdominis muscle in concentrations up to 0.24 micron. Neurotensin and (Gln4)-neurotensin relaxed the rat duodenum at fairly high concentrations (24 nM). The guinea pig ileum contracted in response to increasing doses, although the maximum response were only one half that caused by histamine. Tachyphylaxis was observed at dose intervals of less than 12 minutes, but this tachyphylaxis did not inhibit responses to acetylcholine, histamine, 5-HT or to DMPP, suggesting that the neurotensins may act at specific receptor sites. They contracted the rat fundus strip at concentrations of 0.24 nM and higher. The neurotensins and 5-HT were approximately equipotent on this tissue, although the maximum responses was about 80% of that to 5-HT. The contractions of the rat fundus strip could not be blocked by atropine, hexamethonium, methysergide, morphine or by 7-OH-THC. These data indicate that neurotensin and (Gln4)-neurotensin are equipotent as far as smooth muscle stimulating activity is concerned. Of those organs tested, the rat fundus strip seems to be the most suitable one for studies concerning structure-activity relationships.

beta-Benzamido-alpha-(3-pyridyl)-DL-alpha-alanine hydrochloride was synthesized from 3-pyridinecarboxyaldehyde via the azlactone which was hydrolyzed to the acrylic acid before hydrogenation. The methyl ester was effectively resolved with subtilisin. The optical purity of the D-isomer was established, since the D-isomer was used in synthesis of antagonists of the luteinizing hormone releasing hormone.

A series of antagonists of the luteinizing hormone releasing hormone (LHRH) with substitutions in position 5 and/or 6 that included acylated lysine or p-aminophenylalanine were synthesized, characterized and tested for antiovulatory activity (AOA) in rats, and histamine releasing activity. Some of these antagonists were considerably more soluble at neutral pH than antagonists like Antide. Of 37 new antagonists, the best physico-chemical and biological properties were found for the following two analogs: NAcDNal-DCpa-DPal-Ser-PicLys-D(PicSar)Lys- Leu-ILys-Pro-DAlaNH2 (named Sartide) and NAcDNal-DCpa-DPal-Ser-Tyr-D(PicSar)Lys-Leu-IL ys-Pro-DAlaNH2. They are both soluble in water, inhibit ovulation completely at 0.5 microgram per rat, and have ED50 values for histamine release of about 30 micrograms/mL.

N-Ac-D-O-phenyltyrosine was synthesized via the corresponding azlactone. Resolution of the DL methyl esters was achieved by Subtilisin Carlsberg. Treatment with palladium(II) acetate in trifluoroacetic acid converted N-Ac-D-O-phenyltyrosine into N-Ac-D-3-(2-dibenzofuranyl)alanine. These two amino acids were incorporated instead of N-Ac-D-2-Nal into position 1 of the LHRH-antagonist (N-Ac-D-2-Nal1, D-p-ClPhe2, D-3-Pal3, c-PzACAla5, D-PicLys6, ILys8,D-Ala10)-LHRH. The more rigid N-Ac-D-3-(2-dibenzofuranyl)alanine was structurally more effective than N-Ac-D-O-phenyltyrosine; the AOAs for the corresponding analogs were 82 and 38%, respectively, at 0.5 micrograms. Replacement of c-PzACAla in position 5 by O-phenyltyrosine significantly decreased potency.

Improved cardiovascular morbidity and mortality have been observed in several clinical studies of dietary supplementation with coenzyme Q10 (CoQ10, ubiquinone). Several mechanisms have been proposed to explain the effects of CoQ10. One attractive theory links ubiquinone with the inhibition of platelets. The effect of CoQ10 intake on platelet surface antigens, and certain hemostatic parameters was examined in 15 humans and 10 swine. Study participants received 100 mg of CoQ10 twice daily in addition to their usual diet for 20 days resulting in a three-fold increase of total serum CoQ10 level. We observed a decline in plasma fibronectin (-20.2%), thromboxane B2 (-20.6%), prostacyclin (-23.2%), and endothelin-1 (-17.9%) level. Significant inhibition of vitronectin receptor expression was observed consistently throughout ubiquinone treatment. Inhibition of the platelet vitronectin receptor is a direct evidence of a link between dietary CoQ10 intake, platelets, and hemostasis. These findings may contribute to the observed clinical benefits by a diminished incidence of thrombotic complications in such patients.

Improved cardiovascular morbidity and mortality have been observed in several clinical studies of dietary supplementation with coenzyme Q10 (CoQ10). We elucidated the effect of CoQ10 on certain hemostatic parameters that may influence the progression of heart disease. Twelve Yorkshire swine were randomized to receive diet supplementation with either CoQ10 or placebo for 20 days. Blood samples were obtained at baseline and at the end of the feeding period. At the end of the protocol, there were no significant differences in hemostatic parameters in the placebo group. A significant increase in total serum CoQ10 level (from 0.39 +/- 0.06 to 0.96 +/- 0.04 microgram/ml, p < 0.001) was noted after the feeding period in the CoQ10-supplemented group. We observed significant inhibition of ADP-induced platelet aggregation (-9.9%) and a decrease in plasma fibronectin (-20.2%), thromboxane B2 (TXB2, -20.6%), prostacyclin (-23.2%), and endothelin-1 (ET-1, -17.9%) level. There were no changes in the plasma concentrations of the natural antithrombotics [antithrombin-III (AT-III), protein S, and protein C] after CoQ10 supplementation. CoQ10 supplementation in a dose of 200 mg daily is associated with mild antiaggregatory changes in the hemostatic profile. Clinical beneficial effects of CoQ10 may be related in part to a diminished incidence of thrombotic complications.

Several LHRH antagonists with trans-3-(4-pyrazinylcarbonylaminocyclohexyl)alanine (trans-PzACAla) in the position 5 were synthesized and their antiovulatory activity was compared with the activity of the analogs containing cis-PzACAla in this position. In all cases cis-isomer produced more potent analogs. Introduction of cis-PzACAla in the position 5 of Antide gave Antide B which completely inhibits ovulation at a dose of 0.5µg/rat. Antide B releases negligible histamine (ED50 = 104µg/mL), and has excellent solubility in water. Also, an improved synthesis of cis-PzACAla is reported, involving the hydrogenation of 4-aminophenylalanine on a rhodium catalyst to give the desired cis-isomer with a 53% yield.

We have studied the structure-activity relationship of a series of tachykinin receptor antagonists based on spantide II. Fifteen novel peptides were tested for their ability to antagonize the electrically evoked tachykinin receptor-mediated response in the isolated rabbit iris sphincter muscle. Substitution or deletion of one to three amino acids in the spantide II sequence caused significant changes in biological activity. Eight of the novel analogues were found to be as potent as or more potent than spantide II and some were found to have better water solubility. We tested the selectivity for different tachykinin receptors of spantide II and two of the eight most potent analogues. They all interacted with tachykinin NK1 (rabbit jugular vein) and tachykinin NK2 (rabbit pulmonary artery) receptors with pA2 values of about 6.5-7.5 at the NK1 receptor and of 5.9-7.2 at the NK2 receptor, while being inactive at the tachykinin NK3 receptor (rat portal vein). Spantide II and the novel analogues were without effect on electrically evoked cholinergic responses of the isolated rabbit iris sphincter and on electrically evoked sympathetic responses of the guinea-pig vas deferens; moreover, they were without local anaesthetic-like effects on action potentials of the frog sciatic nerve, which suggests that they do not produce a general neurosuppressive effect. They were as effective as or slightly less effective than spantide II in causing histamine release from rat peritoneal mast cells.

A 40-year-old woman presented with pro found muscle weakness resulting in failure to wean from a ventilator and persistent lactic acidosis after having recovered from a pneumonia complicated by adult respiratory distress syndrome, myocardial infarction, renal failure and shock. She had a 28 year history of chronic anemia and exercise intolerance. Anemia and thrombocytopenia persisted after admission. Nonobstructive hypertrophic cardiomyopathy was present. A stroke-like episode occurred. A mitochondrial myopathy with deficiencies in complexes IV and II was demonstrated, but no DNA defect has yet been found. This patient represents a distinct clinical presentation of a mitochondrial disorder characterized by late onset mitochondrial myopathy, chronic anemia, cardiomyopathy, and lactic acidosis. © 1994 Wiley-Liss, Inc.

The structure-activity data of 6 years on 395 analogs of the luteinizing hormone releasing hormone (LHRH) have been studied to determine effective substituents for the ten positions for maximal antiovulatory activity and minimal histamine release. The numbers of substituents studied in the ten positions are as follows: (41)(1)-(12)(2)-(12)(3)-(5)(4)-(47)(5)-(52)(6)-(16)(7)-(18)(8)-(4)(9)-(8)(10). In position 1, DNal and DQal were effective with the former being more frequently the better substituent. DpClPhe was uniquely effective in position 2. Positions 3 and 4 are very sensitive to change. D3Pal in position 3 and Ser in position 4 of LHRH were in the best antagonists. PicLys and cPzACAla were the most successful residues in position 5 with cPzACAla being the better substituent. Position 6 was the most flexible and many substituents were effective; particularly DPicLys. Leu(7) was most often present in the best antagonists. In position 8, Arg was effective for both antiovulatory activity and histamine release; ILys was effective for potency and lesser histamine release. Pro(9) of LHRH was retained. DAlaNH2 (10) was in the best antagonists.

Alcohol metabolism may result in oxidant stress and free radical injury through a variety of mechanisms. Lovastatin may also produce oxidant stress by reducing levels of an endogenous antioxidant, coenzyme Q (CoQ). The separate and combined effects of ethanol, 20 EN% in a total liquid diet, and lovastatin, 67 mg/kg diet, on alpha-tocopherol, retinol palmitate, CoQ9 and thiobarbituric acid reactive (TBAR) material in liver from rats were determined. The effect of exogenous CoQ10 on these treatment groups was also determined. Food consumption, weight gain, liver lipid and TBAR material were similar between treatment groups. Compared to control animals, ethanol reduced retinol palmitate significantly, from 143 to 90 micrograms/g wet weight. Lovastatin had no effect on retinal palmitate nor did it act additively with ethanol. Ethanol decreased liver alpha-tocopherol from 28 to 12 micrograms/g wet weight and lovastatin diminished it to 12 micrograms; no additive effect was evident. Ethanol had no effect, but lovastatin decreased CoQ9 from 83 to 55 micrograms/g wet weight. Supplementation with CoQ10 did not modulate the effect of ethanol on retinal palmitate, but it did reverse the effect of lovastatin on CoQ9. Supplementary CoQ10 did not alter control levels of alpha-tocopherol, but it appeared to reverse most of the decrease in alpha-tocopherol attributable to ethanol or lovastatin separately. It only partially reversed the effect of ethanol and lovastatin combined on alpha-tocopherol, however. As expected, lovastatin had no effect on CoQ10 levels in supplemented animals. Ethanol, either separately or in combination with lovastatin, diminished liver stores of CoQ10 by almost 40%. We conclude that 20 EN% ethanol given in a liquid diet for 5 weeks is sufficient to lower retinol palmitate and that lovastatin reduces CoQ9. Both diminish alpha-tocopherol, an effect largely overcome by CoQ10 supplementation with either drug alone, but not with the combination. Since many individuals chronically consume the levels of ethanol represented by this experiment, and since a certain number of those also take lovastatin, further research into the possible clinical significance of these observations is warranted.

Twenty-one healthy subjects received oral Coenzyme Q 10 supplementation in soft capsules of 30 mg t.i.d. for 9 months, followed by a withdrawal period of 3 months. Blood samples were taken before start of supplementation, after 3 and 9 months of supplementation, and finally 3 months after withdrawal. Average blood coenzyme Q 10 concentration increased from about 1 mg/l before supplementation to about 2 mg/l after 3 and 9 months of supplementation, and returned to the pretreatment level after withdrawal. The rise of coenzyme Q 10 concentration was statistically significant ( P t -test).

Thiophenes and tetrahydrothiophenes are discussed as separate major divisions in this chapter because there are significant differences in the general methods by which these two similar types of compounds are prepared. The general reactions that lead to the formation of thiophenes may be segregated in the following five general classifications (1) Reaction of the 1,4-difunctional compounds with sulfides; (2) reaction of unsaturated compounds with sulfides; (3) reaction of 1,2-difunctional compounds with thiodiacetic acid and esters; (4) reaction of aryl methyl ketones with sulfides; (5) miscellaneous cyclization reactions. Similarly the reactions that form tetrahydrothiophenes may be grouped into four general classifications: (1) Reaction of 1,4-difunctional compounds with sulfides; (2) Dieckmann cyclization; (3) Catalytic method; (4) miscellaneous methods. All of the above are discussed in this chapter. Keywords: thiophenes; tetrahydrothiophenes; sulfides; succinic acids; 1,4-Difunctional compounds; 1,2-Difunctional compounds; experimental procedures

Sixteen new designs of antagonists of the luteinizing hormone releasing hormone (LHRH) with histidine in position 8 were synthesized, because this position is critical both for antiovulatory activity and the side effect of histamine release. The most potent antagonist was NAcDQal-DpClPhe–D 3 Pal– Ser–cPzACAla–DPicLys– Leu– His – Pro –DAlaNH2, which showed 33% AOA at 0.25 μg. The histamine release was remarkably negligible by an ED50 of 308 μg/ml which is superior to 186 μg/ml for LHRH and comparable to 300 for Antide. The relative basicities of His, Arg, and ILys in position 8 of antagonists appear to influence both the level of potency of AOA and a negligible to a significant release of histamine. The least basic His8-analogs can have the lowest AOA and the highest ED50. The very basic Arg8-analogs can have the highest AOA and the lowest ED50. The moderately basic ILys8-analogs can be a compromise for acceptable levels of potency and safety.

This method has been designed to determine the levels of CoQ10 in human blood which utilizes only one drop of blood (0.05 ml). This method encourages and facilitates more frequent monitoring of blood levels of CoQ10, and of clinical importance, reveals the presence or absence of compliance. CoQ11 was used as an internal standard. The mean recovery of CoQ10 was 96%. The correlation coefficient between using 1.0 ml and 0.1 ml of blood and between using 1.0 and 0.05 ml was 0.997 in the two comparisons. Therefore, it can be accurate to monitor the level of CoQ10 in a-"finger-prick"-drop of blood, and at least 24 such determinations can be conducted in a 2-day period.

A colorimetric has been devised for the assay of β‐erythroidine. It involves the development of a purple color which is assayed by means of a photoelectric colorimeter. This assay is of interest in connection with the need for methods to determine 0‐erythroidine and similar substances in body fluids in the investigation of biological problems. Methods for determining the content of chemotherapeutic agents in body fluids are of increasing importance to clinical evaluation of new drugs. This assay is of further interest in regard to the identification and determination of β‐erythroidine in chemical problems.

Twenty-eight male patients with ischaemic heart disease (IHD) performed OBLA (onset of blood lactate accumulation) exercise stress tests and had muscle biopsies taken from their vastus lateralis muscle the day before coronary bypass grafting. All 28 patients showed the same exercise performance pattern as compared to healthy sedentary, age-matched, controls: a low exercise intensity eliciting a blood lactate concentration of 2.0 mmol x l-1 (WOBLA), WOBLA corresponded to a high fraction (% WOBLA) of WSL (symptom limited or 'maximal' capacity), and a low peak blood lactate concentration. The high % WOBLA and low peak blood lactate indicated a reduced glycogenolytic capacity ('anaerobic' performance). Muscle fibre composition disclosed a high mean value of fast twitch (FT), type II or 'white' muscle fibres, as compared to sedentary healthy controls. This indicated that this patient group constituted an extreme subgroup of the age-matched population. The distorted muscle fibre composition in IHD could reflect both heredity as well as adaptation to physical inactivity, degenerative cytosolic properties, etc. Muscle and blood contents of a mitochondrial electron translocator and nonspecific radical scavenger, ubiquinone or coenzyme Q10(CoQ10), were low, which coincided with an elevated frequency of the fibre subgroup FT(c). The presence of the FT(c) fibre type is assumed to reflect histological trauma.

Summary Twenty years of international open and seven double blind trials established the efficacy and safety of coenzyme Q10 (CoQ10) to treat patients in heart failure. In the U.S., ca . 20,000 patients under 65 years are eligible for transplants, but donors are less than 1/10th of those eligible, and there are many more such patients over 65, both eligible and ineligible. We treated eleven exemplary transplant candidates with CoQ10; all improved; three improved from Class IV to Class I; four improved from Classes III–IV to Class II; and two improved from Class III to Class I or II. After CoQ10, some patients required no conventional drugs and had no limitation in lifestyle. The marked improvement is based upon correcting myocardial deficiencies of CoQ10 which improve mitochondrial bioenergetics and cardiac performance. These case histories, and very substantial background proof of efficacy and safety, justify treating with CoQ10 patients in failure awaiting transplantation.

In the research for more potent antagonists of the luteinizing hormone releasing hormone (LHRH), 13 new peptides with emphasis on arginine in position 8 were designed, synthesized and tested for anti-ovulatory activity (AOA). Two very potent analogs were achieved. N-Ac-D-3-Qal, D-pClPhe, D-3-Pal, Ser, cis-PzACA1a, D-PicLys, Leu, Arg, Pro, D-AlaNH2 showed 63% AOA at 0.125 microgram and 89% at 0.25 microgram, and an ED50 of 30.8 +/- 0.59 and presently may be the most promising antagonist reported. It is named Argtide. N-Ac-D-3-Qal, D-pClPhe, D-3-Pal, Ser, cis-PzACA1a, D-PicLys, Val, Arg, Pro, D-AlaNH2 showed 18% AOA at 0.125 microgram. Arg8 in antagonists may be significant for receptor binding.

Some analogs of Antide and congeners with higher water solubility have been synthesized by substitutions in positions 1, 5 or 6 with hydrophilic residues. In position 1, D-3-Qal has been incorporated in four peptides and D-3-Pal in one peptide. In positions 5 and 6, D and L-3-Pal, PzAla and (DSer)Lys have been tried. In one peptide, D—(AcDSer)Lys was substituted in position 6. Most of the new analogs had lower AOA (antiovulatory activity) than the parent compounds but three potent analogs were identified. The first one, [N — Ac— D — 3-Qal1,DpClPhe2,D— 3-Pal3,c-PzACAla5,D — PicLys6,ILys8,D — Ala10]— LHRH, had 55% AOA at 0.25 μg and 100% at 0.5 μg. Its ED50 for in vitro histamine release was 171 ± 17 μg/ml which is an increase from 49±4.8 μg/ml for the parent compound with N—Ac-D-2-Nal [1]. The second analog, [N — Ac— D — 2-Nal1,DpClPhe2,D — 3-Pal3,PicLys5,D — (DSer)Lys6,ILys8,D—Ala10] — LHRH, had 69% AOA at 0.25 μg and 95% at 0.5 μg. This analog released somewhat more histamine than the parent analog featuring D-PicLys6, the ED50 being 18 μg/ml compared to 93 ± 11 for the parent analog. The third analog is: [N — Ac— D— 2-Nal1,DpClPhe2,D— 3-Pal3,c-PzACAla5,D—PzAla6,ILys8,DAla1]— LHRH. The AOA for this analog was 63% at 0.25 μg and the ED50 for histamine release 88±6.4 μg/ml.

Coenzyme Q 10 (CoQ 10 ) is indispensable to biochemical mechanisms of bioenergetics, and it has a non-specific role as an antioxidant. CoQ 10 has shown a hematological activity for the human and has shown an influence on the host defense system. The T4/T8 ratios of lymphocytes are known to be low in patients with AIDS, ARC and malignancies. Our two patients with ARC have survived four-five years without any symptoms of adenopathy or infection on continuous treatment with CoQ 10 . We have newly found that 14 ordinary subjects responded to CoQ 10 by increases in the T4/T8 ratios and an increase in blood levels of CoQ 10 ; both by p This knowledge and survival of two ARC patients for four-five years on CoQ 10 without symptoms, and new data on increasing ratios of T4/T8 lynphyoytes in the human by treatment with CoQ 10 constitute a rationale for new double blind clinical trials on treating patients with AIDS, ARC and diverse malignancies with CoQ 10 .

The composition of skeletal muscle fibre expressed as a percentage of slow twitch (ST), type I or "red" and fast twitch (FT), type II or "white" were determined in patients with hypertension (HT) or with severe ischaemic heart disease (IHD) and compared to age matched controls. Similarly, exercise capacity expressed as the cycle intensity eliciting a blood lactate concentration corresponding to 2.0 mmol x 1-1 were compared with healthy controls. Both patient groups had a higher percentage of FT fibres with relatively lower exercise capacities than their controls. The exercise capacities were reduced even when the relationship of decreased capacity with the percentage of increased FT was considered. There was an increase IHD but not in HT in patients with fibre subgroup FTc, which most probably reflected fibre trauma. Both patient groups were low in the skeletal muscle mitochondrial electron carrier and unspecific antioxidant ubiquinone, coenzyme Q10 or CoQ10. Patients with IHD but not HT showed, however, a faster fall in the ratio CoQ10 over ST% the higher the percentage value of ST. The ratio reflects the antioxidant activity related to CoQ10 in the fibre hosting most of the oxidative metabolism. A low ratio indicates a risk of metabolic lesion and cell trauma. This could explain fibre plasticity and offer an alternative cause to heredity in elucidating in deviating muscle fibre composition in patients with HT and IHD.

Lovastatin is clinically used to treat patients with hypercholesterolemia and successfully lowers cholesterol levels. The mechanism of action of lovastatin is inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme involved in the biosynthesis of cholesterol from acetyl-CoA. Inhibition of this enzyme could also inhibit the intrinsic biosynthesis of coenzyme Q10 (CoQ10), but there have not been definitive data on whether lovastatin reduces levels of CoQ10 as it does cholesterol. The clinical use of lovastatin is to reduce a risk of cardiac disease, and if lovastatin were to reduce levels of CoQ10, this reduction would constitute a new risk of cardiac disease, since it is established that CoQ10 is indispensable for cardiac function. We have conducted three related protocols to determine whether lovastatin does indeed inhibit the biosynthesis of CoQ10. One protocol was done on rats, and is reported in the preceding paper [Willis, R. A., Folkers, K., Tucker, J. L., Ye, C.-Q., Xia, L.-J. & Tamagawa, H. (1990) Proc. Natl. Acad. Sci. USA 87, 8928-8930]. The other two protocols are reported here. One involved patients in a hospital, and the other involved a volunteer who permitted extraordinary monitoring of CoQ10 and cholesterol levels and cardiac function. All data from the three protocols revealed that lovastatin does indeed lower levels of CoQ10. The five hospitalized patients, 43-72 years old, revealed increased cardiac disease from lovastatin, which was life-threatening for patients having class IV cardiomyopathy before lovastatin or after taking lovastatin. Oral administration of CoQ10 increased blood levels of CoQ10 and was generally accompanied by an improvement in cardiac function. Although a successful drug, lovastatin does have side effects, particularly including liver dysfunction, which presumably can be caused by the lovastatin-induced deficiency of CoQ10.

Eleven analogs of the luteinizing hormone-releasing hormone (LHRH) have been designed, synthesized, bioassayed and compared for antiovulatory activity (AOA) in rats. The emphasis of design was on analogs with D–Ala10, Sar10, D–Ser10, (desGly10, NHEt), D–Abu10, Gly10, and with substitutions in position 5, 6, and 8. High antiovulatory activity was obtained with analogs having D– Ala in position 10. Four earlier analogs, 1, 4, 11 and 13, with D– Ala in position 10, showed 67-100% AOA at 0.25 μg in rats. Analog 1 showed 60% AOA at 0.125 μg. The replacement of D–Ala10 in analog 11 by Sar10 in analog 12, retained activity, 62% vs. 67% AOA at 0.25μg, 100% vs. 90% AOA at 0.5 μg. This analog with Sar10 was the only one that did not show substantial loss of activity upon replacement of D–Ala10.

Two undecapeptide substance P (SP) analogues, Spantide I and Spantide II, were tested for their capacity to block the contractile effect of SP on the guinea pig isolated taenia coli and the contractile effect of electrical stimulation of the rabbit isolated (and atropinized) iris sphincter, and for their capacity to mobilize histamine from rat isolated peritoneal mast cells. Spantide I and Spantide II have one feature in common, namely D-tryptophan in positions 7 and 9. Spantide I: D-Arg, Pro2, Lys3, Pro4, Gln5, Gln6, D-Trp7, Phe8, D-Trp9, Leu10, Leu11-NH2. Spantide II: D-NicLys1, Pro2, 3-Pal3, Pro4, D-Cl2Phe5, Asn6, D-Trp7, Phe8, D-Trp9, Leu10, Nle11-NH2. Both Spantide I and II were found to be competitive antagonists to SP on the taenia coli and to be capable of blocking the electrically induced non-cholinergic contraction of the iris sphincter. Spantide II had higher pA2 value (taenia coli) than Spantide I, 7.7 versus 7.0, and higher pIC50 value (blockade of tachykinin-mediated neurotransmission in iris sphincter), 6.0 versus 5.1. Both Spantide I and II mobilized histamine from rat peritoneal mast cells but Spantide II was less effective. Spantide I and II were tested for antagonistic specificity. Both blocked contractions of the taenia induced by SP and neurokinin A. In the concentration used, Spantide II in addition blocked the response to neurokinin B. The contractions induced by carbachol, 5-hydroxytryptamine, histamine and prostaglandins (F2 alpha and E1) were not affected; the contractile response to bombesin was inhibited by Spantide I but not by Spantide II.

Twenty new analogs of LHRH featured acylated aminocyclohexylalanines and acylated lysines in positions 5,6. (N-Ac-D-2-Nal1,DpC1Phe2,D-3-Pal3,PicLys5, pzACAla6,Val7,Ilys8,D-Ala1O)-LHRH (l00% AOA/0.5ug) and (N-Ac-D-2-Nal1, DpClPhe2 D-3-Pal,PicLys5,D-Piclys6Abu7,D-Ala10-LHRH (50% AOA/0.25ug) were most potent.