Synthesis and biological activity of Substance P C-terminal hexapeptide and heptapeptide analogues

The analogues [Glu(OBzl)¹¹]SP_6–11 and [Glu(OBzl)¹¹]SP_5–11 of the C-terminal hexapeptide and heptapeptide of Substance P have been synthesized by conventional solution methods. In each analogue the SCH₃ group of Met¹¹ is replaced by the COOCH₂C₆H₅ group. The in vitro activity of both analogues has been determined on three biological preparations: guinea pig ileum (GPI), rat vas deferens (RVD), and rat portal vein (RPV). The selectivity for the different receptors has been studied by utilizing atropine-treated guinea pig ileum (GPI + At). The results showed that both analogues are mainly active on GPI through the NK-1 receptor and that both analogues are equipotent to Substance P.     

Synthesis of a potent agonist of substance P by modifying the methionyl and glutaminyl residues of the C-terminal hexapeptide of substance P

Analogues of [Orn⁶]-SP_6-11 have been synthesized in which the Met¹¹ residue is replaced by glutamate γ-alkylesters. These analogues were tested in three in vitro preparations representative of NK-1, NK-2, and NK-3 receptor types. Substitution of the SCH₃ group of the Met¹¹ side chain by a COOR (R = methyl, ethyl, n-propyl, n-butyl, cyclohexyl) group results in analogues which are full agonsists in NK-1 and NK-2 preparations but show little agonist activity in the NK-3 preparation. When the SCH₃ group is replaced by a t-butyl ester group and the resulting analogue is a full agonist in all the above preparations and more active than the parent hexapeptide and SP-OCH₃ at NK-1 receptors. It is concluded that for activity at NK-1 receptors methionine can be replaced by γ-t-butyl glutamate without loss of activity, whilst at NK-2 and NK-3 receptors the above substitution increases the activity of [Orn₆]-SP_6-11. Other γ-alkyl esters of the glutamic acid reduce its biological activity.     

Regular Wide QRS Complex Tachycardia During Atrial Fibrillation in a Patient with Preexcitation Syndrome: A Case Report

AV Conduction in WPW. We report an unusual case of a relatively regular wide QRS complex tachycardia alternating with periods of an irregular narrow QRS complex tachycardia during atrial fibrillation in a patient with Wolff-Parkinson-White syndrome. Both tachycardias resulted from atrial fibrillation, the wide QRS complex tachycardia being due to 2:1 AV conduction of a type I atrial fibrillation across a posteroseptal accessory AV connection.     

Synthesis and biological activity of locust AKH-I and its analogues with modifications at the threonine residues

A convenient method of synthesis, using a combination of solid and liquid phase methodology, for locust Adipokinetic Hormone-I (AKH-I) and its analogues with modifications at the threonine residues are reported. The N-terminal nonapeptide acid of AKH-I is synthesized in the solid phase using the 2-chlorotrityl chloride resin and the Fmoc/t-Bu strategy. Quantitative cleavage of the nonapeptide acid from the resin, with the tert-butyl type side-chain protection intact, is achieved with a mixture of acetic acid/trifluoroethanol/ dichloromethane. The nonapeptide acid is then coupled in solution to the threonine derivatives, H-Thr-NH₂ or H-Thr(Bz1)-NH₂, with the DCC/HOBt method. The efficiency of this approach in the synthesis of AKH-I is demonstrated by the high yields and purity of the synthesized peptides. All the synthesized peptides were tested in two ways: first, in a lipid mobilization assay in locusts in vivo; and second, in a novel assay in vitro concerned with the uptake of radiolabelled acetate into locust tissue. Replacement of the hydroxyl hydrogen in Thr⁵ of locust AKH-I by the bulky and highly lipophilic tert-butyl group reduced the potency markedly, whereas efficacy is unaffected, but when the hydroxyl hydrogen of Thr¹⁰ in AKH-I is replaced by a benzyl group, the activity of the resulting analogue is identical to that of the natural peptide. Structure-activity relationships are discussed. © Munksgaard 1994.     

Polymorphic Ventricular Tachycardia Induced During Tilt Table Testing in a Patient with Syncope and Probable Dysfunction of the Sinus Node

We present a case of life-threatening arrhythmia occurring during tilt table testing in a 44-year-old man with syncope. Polymorphic ventricular tachycardia occurred while the patient was tilted up under the intravenous infusion of isoproterenol (2 μg/min). No ischemia, QTc prolongation, or electrolyte abnormality preceded this event. The arrhythmia was not induced by programmed ventricular stimulation or exercise testing. Based on electrophysiological and clinical data, the diagnosis of sick sinus syndrome was entertained.     

Time domain analysis of the signal averaged electrocardiogram in patients with a conduction defect or a bundle branch block

Doubts have been expressed about the clinical usefulness oftime domain analysis of the signal averaged electrocardiogramin patients with prolonged QRS complex duration. We studied147 patients using a signal averaged ECG (40–250 Hz) whoseQRS complex was longer than 100 ms. A baseline electrophysiologystudy was also performed in 128 of these patients. Seventy-sevenpatients had a minor (QRS <120 and >100 ms) conductiondefect. Thirty-seven of these 77 had either induced or spontaneoussustained ventricular tachycardia (group I) and 40 had no sustainedventricular tachycardia (group II). Seventy patients had a major(QRS120 and >100 ms) conduction defect, 44 of whom had sustainedventricular tachycardia (group A). The remaining 26 withoutthis condition formed Group B. Group I compared to group IIpatients had a longer filtered QRS duration (120·8 ±14 vs 104·5 ± 9·5 ms, P<0·001),a longer low amplitude signal duration (41 ± 12·1vs 31 ± 12·6 ms, P<0·0001) and a lowerroot mean square of the last 40 ms of the filtered QRS complex(27 ± 29·8 vs 35 ± 25·3 µV,P=ns). Group A compared to group B had a longer filtered QRSduration (157·7±20·2 vs 140·7±15·7 ms, P<0·001), a longer low amplitude signalduration (57·3 ±24·9 vs 37·8 ±20·3 ms P<0·001) and a lower root mean squareof the last 40 ms of the filtered QRS complex (14·3 ±11·2 vs 22·0 ± 10·5 1 P<0·01).Using conventional late potential criteria, the sensitivityand specificity of the signal averaged ECG for the detectionof sustained ventricular tachycardia patients with a minor conductiondefect were 89% and 75%, respectively. The same criteria appliedto patients with a major conduction defect were sensitive (sensitivity:87%) but non-specific (specificity: 50%). However, by usingmodified late potential criteria, such as the presence of twoof any of the following three signal averaged parameters: filteredQRS duration 145 ms, low amplitude signal duration 50 ms,root mean square of the last 40 ms of the filtered QRS complex17·5µV, we derived a non-optimal but still acceptablecombination of sensitivity (68%) and specificity (73%). We concludethat traditional late potential criteria can be applied in patientswith a minor conduction defect, but modification of these criteriais necessary to derive useful clinical information for riskstratification of patients with a QRS complex duration 120ms.     

Synthesis of potent agonists of Substance P by replacement of Met11 with Glu(OBzl) and N-terminal glutamine with Glp of the C-terminal hexapeptide and heptapeptide of Substance P

The analogues [Glp⁶,Glu(OBzl)¹¹]SP_(6-11) and [Glp⁵,Glu(OBzl)¹¹]SP_(5-11)) of the C-terminal hexapeptide and heptapeptide of Substance P have been synthesized by conventional solution methods. In each analogue the N-terminal glutamine has been replaced by pyroglutamic acid, while the COOCH₂C₆H₅ ester group has replaced the SCH₃ group of the Met¹¹ side chain. The in vitro activity of both analogues has been determined on three biological preparations: guinea pig ileum (GPI), rat vas deferens (RVD) and rat portal vein (RPV). The results showed that both analogues are highly potent and selective agonists on GPI through the NK-1 receptor. They are more potent than SP itself, with 1.54 and 1.25 respective values of relative potency on GPI. Their selectivity has been studied by utilizing atropine-treated guinea pig ileum (GPI + At). The analogues showed low activity on RVD and RPV tissues, which represent NK-2 and NK-3 monoreceptor assay, respectively. © Munksgaard 1995.     

Spontaneous Twisting of an Implanted Pacemaker Electrode in Three Cases

We present three cases of an unusual pacing lead aberration occurring at different times after implantation. In the first patient, the electrode was twisted close to the pacemaker, and dislodgment occurred on the 40th postoperative day. In the second case, there was only proximal twisting of the electrode. In the third case the electrode was twisted in two places: proximal to the pacemaker, and distal, within the right atrium. The complication was managed successfully by reimplanting the same electrode after stiffening the lead near the generator with a portion of the stylet.