Predictors of outcome in patients with papillary thyroid carcinoma.

AIM OF THE STUDY: To evaluate prognostic factors with respect to the outcome in a consecutive series of patients with papillary thyroid carcinoma (PTC) treated at the same institution during a 20-year-period, and to evaluate further the predictive ability of outcome of the pTNM, AMES and MACIS prognostic systems in these patients. MATERIALS AND METHODS: Two hundred and twenty consecutive patients operated on for primary PTC at the Karolinska Hospital between 1980 and 1999 were examined retrospectively. Patient and tumour characteristics at the time of surgery were compared to the patients' outcomes. Univariate and multiple logistic regression analyses were used to identify independently significant prognostic factors with respect to the outcome. In addition, the classification of the patients according to the pTNM, AMES and MACIS prognostic systems were compared to the outcomes. RESULTS: At the end of the follow-up period 201 patients were still alive without disease, 6.5% had died from PTC and 2.5% were alive with persisting disease. In 16 patients, radical surgery could not be performed due to extensive tumour growth and/or distant metastases. Recurrences were detected in 14% of the patients considered as radically operated. The strongest independent predictors for local or distant recurrences and poor clinical outcome were the lack of radical surgery and increasing tumour size. In this investigation MACIS appeared to be the better system, regarding efficacy in predicting the outcome of PTC. CONCLUSION: Removal of all tumour tissue appears most important to a favorable outcome and in our patients MACIS appears the most useful prognostic system taking completeness of resection into account.

Incidence of malignant thyroid tumors in humans after exposure to diagnostic doses of iodine-131. I. Retrospective cohort study.

Between 1952 and 1965, 10,133 patients received an average of 60 mu Cl of 131I for diagnostic examinations of the thyroid gland. The examinations were mainly done on adults, and only 5% of the patients were younger than 20 years at the time of examination. Of the patients, 9 appeared in the Swedish Cancer Registry between 1958 and 1977 with a diagnosis of malignant tumor of the thyroid gland more than 5 years after the administration of 131I. Inasmuch as the expected number of malignant thyroid tumors computed from Swedish cancer incidence figures was 8.3, there was no elevation of the incidence of malignant thyroid tumors in these patients receiving diagnostic doses of 131I. The patients were examined because of a suspected thyroid dysfunction and therefore represented a selected group. The investigation is being continued to analyze further parameters that could have a bearing on these results.

Incidence of malignant thyroid tumors in humans after exposure to diagnostic doses of iodine-131. II. Estimation of thyroid gland size, thyroid radiation dose, and predicted versus observed number of malignant thyroid tumors.

The size of the thyroid glands was analyzed for 10% of the patients in a selected group that had been exposed to diagnostic doses of 131I. The mean thyroid gland weight +/- SD was 50 +/- 33 g for patients 20 or more years of age and 10 +/- 5 g for patients less than 20 years of age. With the present follow-up, diagnostic doses of 131I appeared not to be associated with an increased risk for later development of malignant thyroid tumors. Possible reasons for the difference between the observed number of such tumors and the number expected (47-124) on the basis of risk estimates of the United Nations Scientific Committee on the Effects of Atomic Radiation are discussed.

Cancer risk after iodine-131 therapy for hyperthyroidism.

Cancer incidence was studied in 10,552 patients (mean age, 57 years) who received 131I therapy (mean dose, 506 MBq) for hyperthyroidism between 1950 and 1975. Follow-up on these patients was continued for an average of 15 years. Record linkage with the Swedish Cancer Register for the period 1958-1985 identified 1543 cancers occurring 1 year or more after 131I treatment, and the standardized incidence ratio (SIR) was 1.06 (95% confidence interval = 1.01-1.11). Significantly increased SIRs were observed for cancers of the lung (SIR = 1.32; n = 105) and kidney (SIR = 1.39; n = 66). Among 10-year survivors, significantly elevated risks were seen for cancers of the stomach (SIR = 1.33; n = 58), kidney (SIR = 1.51; n = 37), and brain (SIR = 1.63; n = 30). Only the risk for stomach cancer, however, increased over time (P less than .05) and with increasing activity administered (P = not significant). The risk for malignant lymphoma was significantly below expectation (SIR = 0.53; n = 11). Overall cancer risk did not increase with administered 131I dose or with time since exposure. The absence of any increase in leukemia adds further support to the view that a radiation dose delivered gradually over time is less carcinogenic than the same total dose received over a short time. Only for stomach cancer was a possible radiogenic excess suggested.

Thyroid cancer after diagnostic doses of iodine-131: a retrospective cohort study.

The incidence of thyroid cancer was evaluated in 35,074 patients examined for suspected thyroid disorders between 1951 and 1969 with an average of 1.92 megabecquerel [(MBq) 52 microCi] of 131I. The radiation dose to the thyroid gland was, on the average, approximately 0.5 Gy. The mean age at the time of examination was 44 years; 5% were under age 20. Patients were followed for an average of 20 years. Record linkage with the Swedish Cancer Register identified 50 thyroid cancers occurring 5 years or more after the initial 131I examination, in contrast to 39.4 expected based on general population rates [standardized incidence ratio (SIR) = 1.27, 95% confidence interval = 0.94-1.67]. Risk was highest among males (SIR = 2.70, n = 10), patients followed 5-9 years (SIR = 2.22, n = 23), and patients receiving more than 74 microCi or 2.74 MBq of 131I (SIR = 2.04, n = 17). However, these observations were confounded by the fact that patients examined for a suspected thyroid tumor received the highest 131I exposures and were at highest overall risk (SIR = 2.77, n = 34). Patients given 131I for reasons other than a suspected tumor were not at increased risk (SIR = 0.62, n = 16). Patients anticipated to be at highest risk, i.e., women (SIR = 1.12, n = 40) and those observed for 10 years or more (SIR = 0.93, n = 27), showed no evidence of a dose response. Overall, these data provide little proof that 131I is carcinogenic in humans and support the notion that the carcinogenic potential of internal 131I beta particles might be as low as four times less than external x rays or gamma rays.

Cancer risk in population examined with diagnostic doses of 131I.

Previously, we conducted a study of 35,074 patients receiving diagnostic doses of 131I for suspected thyroid disorders between 1951 and 1969. We reported that, between 1958 and 1984, the incidence of thyroid cancers in these patients was insignificantly greater than the incidence expected in the general population. This increase was attributed to the underlying condition that prompted the examination and not to the administration of 131I. The purpose of the present study was to analyze the total cancer risk in the same cohort of patients examined with diagnostic doses of 131I. To further evaluate the underlying risk of disease in these patients, we compared the incidence of all cancers with that expected in the general population. The average radiation dose was approximately 500 mGy to the thyroid and less than 10 mGy to other organs. In the 35,074 patients, 3,746 cancers occurred following the first 5 years after examination, and the resulting standardized incidence rate (SIR) was 1.01 (95% confidence interval = 0.98-1.04). SIRs were significantly increased for endocrine tumors other than thyroid cancer (1.93) and for lymphomas (1.24), leukemias (1.34), and nervous system tumors (1.19). The risk of leukemia was similar for chronic lymphocytic leukemia (CLL) (SIR = 1.30) and non-CLL (SIR = 1.34). SIR was significantly decreased for cancers of the female genital organs (0.86). The risk for cancer of all sites and types combined was highest 5-9 years after examination (SIR = 1.07) and did not differ from unity thereafter. With greater than or equal to 10 years of follow-up, risk was not statistically associated with the dose of 131I. Overall, the data exclude cancer risk increments greater than 5% (SIR = 1.05) with 95% confidence. The significant increase in the risk of non-CLL, a prominent radiogenic malignancy, however, warrants special attention. We are continuing our study to determine the possible factors involved in the significant increase in the risk of leukemia.

Comparison of nuclear DNA content in primary and metastatic papillary thyroid carcinoma.

Nuclear DNA values were determined in 40 primary papillary thyroid carcinomas, as well as in 52 corresponding local recurrences and metastases were observed either at the time of diagnosis or up to 20 years later. The patient population consisted of 34 survivors and 6 nonsurvivors. In survivors, both the primary tumors and their recurrences and metastases exhibited a majority of cells with DNA values within the normal diploid region, whereas nonsurvivors showed increased and scattered DNA values. In all cases, the primary tumors and the corresponding recurrences and metastases showed similar DNA distribution patterns even if many years had passed between the detection of the primary tumor and the metastases. The results indicate that in papillary thyroid carcinomas, the DNA distribution patterns in the primary tumor and the corresponding recurrences or metastases are generally similar throughout the entire period of disease.

A structurally unique, potent, and selective oxytocin antagonist derived from Streptomyces silvensis.

The in vitro and in vivo oxytocin/arginine vasopressin (OT/AVP) antagonist properties of two cyclic hexapeptides derived from a newly discovered natural product (L-156,373) of Streptomyces silvensis are described. In radioligand binding assays, L-156,373 [cyclo(L-Pro-D-Phe-N-OH-L-Ile-D-piperazyl-L-piperazyl-N-Me-D -Phe)] exhibited moderate affinity for rat uterine OT receptors (Ki, 150 nM), with some selectivity (approximately 20-fold) vs. liver AVP-V1 and kidney AVP-V2 receptors. Dehydroxylation of N-hydroxyisoleucine and oxidation of the piperazic acid residues of L-156-373 produced an interesting derivative, L-365,209. These structural modifications increased OT receptor affinity and selectivity by 20- and 2.5-5-fold, respectively. In the isolated rat uterus, L-365,209 was a potent (apparent dissociation constant, 1.7 nM) and competitive OT antagonist. L-365,209 also blocked the effects of AVP at both AVP-V1 (phosphatidylinositol turnover in rat hepatocytes) and AVP-V2 (adenylate cyclase in rat kidney medulla) receptors, but only at low micromolar concentrations. L-365,209, given iv to anesthetized rats, antagonized the action of exogenous OT on the uterus (ID50, 460 micrograms/kg) with a relatively long duration of action. L-365,209 represents a unique class of compounds that provides an entirely new approach for the design of antagonists for these neurohypophyseal hormones.

Graves' hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine--a prospective, randomized study. Thyroid Study Group.

To analyze the benefits and risks of three common treatments, we randomly assigned 179 patients with Graves' hyperthyroidism as follows: 60 patients, 20-34 yr of age (young adults), received antithyroid drugs for 18 months (medical) or subtotal thyroidectomy (surgical), and 119 patients, 35-55 yr of age (old adults), received medical, surgical, or radioiodine (iodine-131) treatment. The follow-up time was at least 48 months. Antithyroid drugs, surgery, or iodine-131 treatment normalized the mean serum hormone levels within 6 weeks. The risk of relapse was highest in the medically treated young and old adults (42% vs. 34%), followed by that in those treated with iodine-131 (21%) and that in the surgically treated young and old adults (3% vs 8%), respectively. Elevated TSH receptor antibodies at the end of medical therapy or increasing TSH receptor antibodies values after medical or surgical treatment increased the probability of relapse. Development or worsening of ophthalmopathy was not associated with relapse per se. Ninety percent of the subjects in all groups were satisfied with the treatment they received. No significant difference in sick-leave due to Graves' or other diseases was seen during the first 2 yr after initiation of therapy. The increased risk of ophthalmopathy in patients with high serum T3 levels, especially when treated with iodine-131, and the relatively high frequency of relapse after treatment with antithyroid drugs are important factors to consider when selecting therapy for Graves' disease.

Different dose regimens of 5-fluorouracil and interferon-alpha in patients with metastatic colorectal carcinoma.

Three different 5-fluorouracil (5-FU)-interferon-alpha-2b (IFN)-containing regimens were designed for treatment of patients with advanced colorectal cancer. 87 patients with a Karnofsky index > or = 70 were included in three sequential non-randomised phase II trials. Regimen A consisted of 5-FU (750 mg/m2/day) given as a continuous infusion on days 1-5 followed by weekly 1-h intravenous infusions until week 8. IFN (5 MU) was given subcutaneously on days 1, 3 and 5 followed by injections (9 MU) every second day until week 8. The cycle was then repeated. Regimen B consisted of 5-FU (750 mg/m2/day) given as a continuous infusion on days 1-5 followed by 5-min intravenous injections on days 12 and 19. IFN (3 MU) was given subcutaneously on days 1-5 followed by injections (5 MU) on days 11-13 and 18-20. The cycle was repeated every fourth week. Regimen C consisted of 5-FU (750 mg/m2/day) given as a continuous infusion on days 1-5. IFN (3 MU) was given subcutaneously on days 1-5. The cycle was repeated every third week. The objective response rates (complete response (CR) and partial response (PR)) after approximately 4 months of therapy or longer were as follows: regimen A (n = 27) 22% (2 CR, 4 PR), regimen B (n = 33) 42% (4 CR, 10 PR) and regimen C (n = 27) 22% (1 CR, 5 PR). The corresponding response figures for previously untreated patients were regimen A 50%, regimen B 64% and regimen C 38%. Response durations varied from a few weeks up to 142 + weeks. Toxicities were generally mild and reversible, and the treatments were convenient for the patients and cost effective since the 5-day infusions could be given by a portable pump without hospitalisation. Our results are in agreement with those of others showing that 5-FU/IFN combinations can be highly effective in advanced colorectal cancer, and that a number of factors such as doses, dose intensities, infusion rates and timing of the two drugs may be crucial for the anti-tumour activity of this drug combination.

Changes of the blood lymphocyte population following 131I treatment for nodular goiter.

The blood lymphocyte population was examined in 34 patients who were treated with 131I for toxic or atoxic nodular goiter. The patients received one to three doses of 300-550 MBq of 131I administered at 1 week intervals. Lymphocyte counts were significantly reduced both 1 and 6 weeks after treatment. This reduction was accompanied by a changed composition of the lymphocyte population. The frequency of lymphocytes expressing membrane receptors for C'3 (EAC-rosette forming) was significantly reduced 1 and 6 weeks after 131I-administration. At 6 weeks there was a slight but statistically significant increase of the frequency of T-cells as identified by Leu 1 monoclonal antibodies. This was largely caused by an increased proportion of helper/induced T-cells as identified by Leu 3a monoclonals. 131I-treatment also reduced the capacity of lymphocytes to secrete immunoglobulins (Ig) upon PWM-stimulation. The most pronounced effect was observed for IgM. Secretion of IgG and IgA were less reduced. Mitogenic stimulations of lymphocytes with PHA and ConA were not significantly changed. We conclude that these changes observed, with the exception of mitogen reactivity, are essentially similar to those occurring after external radiation therapy for cancer. We speculate that blood lymphocytes passing through the continuously irradiated gland are damaged mainly by emitted beta-particles.

External irradiation of growth hormone producing pituitary adenomas: prolactin as a marker of hypothalamic and pituitary effects.

Fifty-six patients with acromegaly were treated with external irradiation, 50 Gy, after unsuccessful pituitary surgery. A 50% reduction of pre-irradiation growth hormone levels was obtained in 51/56 patients. This level was reached after 26 +/- 14 months in 33 patients with prolactin levels less than 25 micrograms/l at diagnosis, after 21 +/- 17 months in 18 patients with prolactin greater than or equal to 25 micrograms/l, and after 20 +/- 21 months in 12 patients with prolactin greater than 40 micrograms/l at diagnosis. A further 50% decrease of growth hormone levels was obtained in 40/51 patients 42 +/- 22 months after radiotherapy, indicating that in clearly responsive patients, the growth hormone depression after radiotherapy follows a first order reaction. Four patients did not reach a 50% reduction of growth hormone levels 48-80 months after radiotherapy. During 10 years of follow-up, the growth hormone depression tended to be more pronounced in patients with mixed secretion of growth hormone and prolactin. The reduction of growth hormone levels was not correlated with the irradiated volume or the cumulative radiation effect. Within the first year, prolactin increased within the normal range in normoprolactinemic patients and remained so during follow-up. In hyperprolactinemic patients, prolactin decreased successively but to a lesser extent than growth hormone. Pituitary insufficiencies increased over time and three patients developed GH-insufficiency. Hypothalamic damage as indicated by prolactin changes was a regular phenomenon after radiotherapy.

Hypothyroidism after external radiotherapy for head and neck cancer.

PURPOSE: To study the development of thyroid hypofunction in patients with head and neck cancers admitted for external radiotherapy. METHODS AND MATERIALS: Between November 1990 and July 1996, thyroid function was measured in 264 consecutive patients, where the entire thyroid gland or part of it was included in the target volume. The time to development of hypothyroidism (HT) was calculated from the start of the radiotherapy. RESULTS: The median follow-up period was 19 months. Seventeen patients (6%) developed elevated serum thyroid-stimulating hormone levels with depressed (free) thyroxine levels (i.e., clinical HT). Elevated serum thyroid-stimulating hormone level with normal (free) thyroxine levels (i.e., chemical HT) developed in 57 (22%). The median time to clinical HT was 15 months (range: 7 to 32). The median time to chemical HT was also 15 months (range: 2 to 28). The actuarial risk of developing clinical or chemical HT 3 years after treatment was 15 and 40%, respectively. The incidence of chemical HT was significantly higher (p = 0.041) when the whole thyroid was included in the target volume compared to patients where only part of the thyroid was irradiated. The same trend was seen as regards clinical HT (p = 0.063). For those 20 patients who underwent laryngectomy, there was an increased risk of both chemical and clinical HT (p = 0.011 and 0.019, respectively). Increasing age was associated with an increased risk of chemical HT (p = 0.001), but not of clinical HT (p = 0.553). Sex, tumor site, radiation dose, and combination of radiotherapy and chemotherapy were not significant factors for thyroid hypofunction. CONCLUSION: Depressed thyroid function is common after external radiotherapy for cancers of the head and neck. Routine testing for possible thyroid hypofunction should be included in the follow-up procedures, even many years after end of radiotherapy.

Prognostic impact of complete remission after preoperative irradiation of tonsillar carcinoma: a retrospective analysis of the radiumhemmet data, 1980-1995.

PURPOSE: This retrospective study was done to determine the outcome of patients with tonsillar carcinoma treated at Radiumhemmet, Karolinska Hospital, between January 1980 and December 1995 with radiotherapy alone or in combination with surgery. In addition the importance of tumor remission for patient survival was analyzed. METHODS AND MATERIALS: The analysis is based on 167 previously untreated patients with biopsy-proven, invasive tonsillar squamous cell carcinoma of the tonsillar region. All patients were consecutively admitted to the Department of General Oncology, Radiumhemmet, and treated with curative intent. The median follow-up time was 20 months. The median target dose was 64 Gy, delivered in fractions of 2 Gy 5 times weekly. Twenty-eight percent of the patients underwent surgery of the primary site and/or neck dissection after radiotherapy (RT). RESULTS: The overall local control rate for the whole patient group after radiotherapy was 79%. Probability of survival after 5 years for patients responding with complete remission (CR) was 43% and for patients with incomplete response (non-CR) 9%, (p<0.0001). The survival in the non-CR group treated with combination therapy was 20 months longer than in patients receiving radiotherapy alone (p<0.0001). There was no statistically significant difference in prediction of long-term survival when the patient population was stratified according to tumor differentiation grade, age, sex, nodal status, or treatment time. CONCLUSION: The strongest clinical predictor of survival was the degree of tumor remission after RT. For the non-CR group receiving combination treatment including surgery there was a survival benefit as compared to patients treated with RT alone (p<0.0001) although there were few long-term survivors in this patient group.

Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists.

3-(Acylamino)-5-phenyl-2H-1,4-benzodiazepines, antagonists of the peptide hormone cholecystokinin (CCK), are described. Developed by reasoned modification of the known anxiolytic benzodiazepines, these compounds provide highly potent, orally effective ligands selective for peripheral (CCK-A) receptors, with binding affinities approaching or equaling that of the natural ligand CCK-8. The distinction between CCK-A receptors on the one hand and CNS (CCK-B), gastrin, and central benzodiazepine receptors on the other is demonstrated by using the structure-activity profiles of the new compounds. Details of the binding of these agents to CCK-A receptors are examined, and the method of development of these compounds is discussed in terms of its relevance to the general problem of drug discovery.

Nanomolar-affinity, non-peptide oxytocin receptor antagonists.

Non-peptide antagonists of the peptide hormone oxytocin (OT) with nanomolar OT receptor affinities are described. These compounds incorporate novel amido- and amidoalkylcamphor variations to the lead structure L-366,509 (1) to achieve receptor affinity enhancements of 2-3 orders of magnitude over that compound. The new OT antagonist L-367,773 (35) is shown to be an orally bioavailable agent with good duration in vivo and to inhibit OT-stimulated uterine contractions effectively in several in vitro and in vivo models.

Development of a novel class of cyclic hexapeptide oxytocin antagonists based on a natural product.

A new structural class of cyclic hexapeptide oxytocin antagonists derived from Streptomyces silvensis and typified by L-365,209 (cyclo-[L-prolyl1-D-phenylalanyl2-L- isoleucyl3-D-dehydropiperazyl4-L-dehydroperazyl5-D-(N- methyl)phenylalanyl6]) was recently reported. In this paper we further delineate the structure-activity profile for this new class by systematic study of L-365,209 analogs obtained by total synthesis. The optimal combination of cyclic amino acid ring sizes at positions 1, 4, and 5 and the role of the N-alkyl substituent at position 6 was elucidated. The lipophilic amino acids at positions 2 and 3 and the unusual amino acid D-dehydropiperazic acid at position 4 were found to be the most critical residues for obtaining good oxytocin receptor affinity. Analogs containing a basic side chain at the less critical 5- and 6-positions maintained good receptor affinity and also had useful levels of water solubility for intravenous formulation. By combining potency- and solubility-enhancing substitutions, several analogs were identified that have the desired combination of properties in vitro (22, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-pipecolyl-L-pipeco lyl-D- histidyl]; 25, cyclo-[L-prolyl-D-2-naphthylalanyl-L-isoleucyl-D-pipecolyl-L -pipecolyl-D- histidyl]; 26, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-dehydropiperazyl-L-++ pipecolyl-D-histidyl]; 33, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-pipecolyl-L- piperazinylcarboxy-D-(N-methyl)phenylalanyl]; 34, cyclo-[L-prolyl-D-phenylalanyl-L-isoleucyl-D-dehydropiperazyl-L-or nithyl- D-(N-methyl)phenylalanyl]). In general, this class exhibited good selectivity for binding to the oxytocin receptor versus the arginine vasopressin V1a and V2 receptor subtypes, although increased V2 receptor affinity was observed in one case (32, cyclo[L-prolyl-D-2-naphthylalanyl-L-isoleucyl-D-pipecolyl-L- lysyl-D-(N- methyl)phenylalanyl]). Unexpectedly, compound 33 was found to stimulate contractions of the isolated rat uterus via activation of the uterine bradykinin receptor. Compounds 22, 25, 26, 33, and 34 were found to be potent antagonists of oxytocin-stimulated contraction of the rat uterus in vitro and in vivo. Compounds 22 and 25 were additionally characterized as potent antagonists of oxytocin-stimulated uterine contractions in the near-term pregnant rhesus monkey. These studies thus demonstrate the selectivity and efficacy of certain members of this novel class of antagonists and suggest their use as pharmacological tools in further defining the role of oxytocin in both term and preterm labor.

Orally active, nonpeptide oxytocin antagonists.

The first nonpeptide antagonists of the neurohypophyseal hormone, oxytocin (OT) are described. Derivatives of the spiroindenepiperidine ring system, these compounds include L-366,509, an orally bioavailable OT antagonist with good in vivo duration. The potential use of these agents for treatment of preterm labor and their significance as new nonpeptide ligands for peptide receptors are discussed.

Design of nonpeptidal ligands for a peptide receptor: cholecystokinin antagonists.

A series of 3-substituted 5-phenyl-1,4-benzodiazepines, nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK), have been synthesized. Designed on the basis of facts regarding CCK, its natural-product antagonist asperlicin (3), and the antianxiety agent diazepam (4), these compounds represent a significant departure from existing CCK antagonists. They also constitute perhaps the first examples of simple, nonpeptidal ligands for a peptide receptor to arise by design rather than by screening. These compounds serve to illuminate the distinction between central and peripheral CCK receptors, as well as to provide orally effective CCK antagonists of potential pharmacological or therapeutic utility. One rationale for their receptor affinity has possible applications in the design of nonpeptidal ligands for other receptors, peptidal as well as nonpeptidal.

Antihypertensive beta-adrenergic blocking agents: N-aralkyl analogues of 2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine.

An interest in dual-acting antihypertensive agents, specifically those related to (S)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine (1), led us to probe the contribution of the side-chain amino substituent in this series. The ability of 1 and its various analogues to displace radiolabeled alpha 1 (WB-4101 and prazosin) and beta (dihydroalprenolol) adrenergic receptor ligands was assessed by receptor-binding techniques. Most of the compounds exhibited high beta-adrenoceptor binding affinities, but only the N-aralkylamino-substituted compounds showed high alpha 1-adrenoceptor affinities. Therefore, the vasodilation shown by 1 was not due to an interaction with the alpha 1 adrenoceptor. The aralkylamino analogues of 1 in spontaneously hypertensive rats and anesthetized dogs exhibited antihypertensive activity and alpha 1-adrenoceptor blocking properties. Unlike the preference shown by beta-adrenoceptors for S enantiomers in this oxymethylene class of beta blockers, the chirality at the secondary hydroxy center made only a minor contribution to the affinity for the alpha 1-adrenoceptor and even less of a contribution to the observed antihypertensive effects. This lack of chiral influence at the hydroxy center confirmed what had been previously observed in more limited studies with the isomers of both labetalol and medroxalol.